Functional Recovery in Major Depressive Disorder: Providing Early Optimal Treatment for the Individual Patient

Functional Recovery in Major Depressive Disorder: Providing Early Optimal Treatment for the... Major depressive disorder is an often chronic and recurring illness. Left untreated, major depressive disorder may result in progressive alterations in brain morphometry and circuit function. Recent findings, however, suggest that pharmacotherapy may halt and possibly reverse those effects. These findings, together with evidence that a delay in treatment is associated with poorer clinical outcomes, underscore the urgency of rapidly treating depression to full recovery. Early optimized treatment, using measurement-based care and customizing treatment to the individual patient, may afford the best possible outcomes for each patient. The aim of this article is to present recommendations for using a patient-centered approach to rapidly provide optimal pharmacological treatment to patients with major depressive disorder. Offering major depressive disorder treatment determined by individual patient characteristics (e.g., predominant symptoms, medical history, comorbidities), patient preferences and expectations, and, critically, their own definition of wellness provides the best opportunity for full functional recovery. Keywords: depression, function, pharmacotherapy, treatment optimization Introduction Major depressive disorder (MDD) is the leading cause of disabil- symptoms, individuals with MDD experience impairments in ity worldwide, affecting an estimated 350 million individuals physical, occupational, and social functioning (Kessler et  al., globally (World Health Organization, 2012). In addition to mood 2003; American Psychiatric Association, 2013). Their return to Received: May 31, 2017; Revised: August 11, 2017; Accepted: September 7, 2017 © The Author(s) 2017. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 128 provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Oluboka et al. | 129 previous functioning may have a slower trajectory compared in various brain areas, including the hippocampus ( Videbech with symptomatic improvement during treatment (Miller et al., and Ravnkilde, 2004; McKinnon et al., 2009; MacQueen and Frodl, 1998; Bech, 2005; Papakostas, 2009; IsHak et  al., 2011). Ongoing 2011). Hippocampal volume loss is more severe in patients with functional impairment may interfere with integration back into a longer duration of untreated depression (Sheline et al., 2003 ; daily life and in turn delay full functional recovery. Conversely, McKinnon et al., 2009; MacQueen and Frodl, 2011). More recently, a higher level of functioning at baseline may be associated with research has focused on whether antidepressant treatment can better outcomes after treatment (McIntyre et al., 2017). alter the course of brain deficits associated with MDD ( Duric and The Canadian Network for Mood and Anxiety Treatments Duman, 2013; Rotheneichner et al., 2014). To underscore the need (CANMAT) recommends pharmacotherapy as a first-line for optimizing treatment for patients with depression as rapidly treatment for moderate to severe MDD (Kennedy et  al., 2016 ). as possible, we review here English language publications over Numerous antidepressants are available for the treatment of the past 5 years examining effects of depression and antidepres- MDD, including selective serotonin reuptake inhibitors (SSRIs), sant treatment on hippocampal volume. While other brain areas serotonin–norepinephrine reuptake inhibitors, and other anti - have also been examined, we focused this discussion on the depressants (agomelatine, bupropion, mianserin, mirtazapine, hippocampus as an example, because it has been examined in and vortioxetine), all of which have Level 1 evidence and are numerous studies in treated and untreated depressed patients therefore recommended as first-line treatments ( Kennedy et al., in both cross-sectional and longitudinal studies. Excluding 2016). Despite the range of pharmacotherapy options, treatment bipolar and psychotic depression, our search yielded a total of of MDD to full symptomatic and functional recovery remains 235 articles. A  total of 33 primary articles reported research in challenging. Rates of remission are low for any given drug human depression, 19 of which were found to be relevant and (approximately ≤50%) across groups of patients evaluated in are summarized below (Table 1). antidepressant clinical trials (Thase et al., 2005 ; Machado et al., Recently published research identified in this search con - 2006) and may be lower among patients treated in clinical prac- firmed earlier findings that depression is associated with altera - tice (Trivedi et al., 2006; Moller, 2008). The achievement of both tions in brain morphometry and circuit dysfunction that can be symptom remission and full functional recovery after a trial observed as volume loss in the hippocampus and other areas of an antidepressant treatment is even more difficult ( Soares implicated in depression (Geerlings et  al., 2012; Sheline et  al., et al., 2014b), and functional recovery can lag behind symptom 2012; Arnone et al., 2013; Huang et al., 2013; Nugent et al., 2013 ; remission (Sheehan et al., 2011 ). Therefore, successful manage- Zhao et  al., 2014; Schmaal et  al., 2016). A  significant reduction ment of MDD necessitates development of a personalized treat - in hippocampal volume has been reported as early as the first ment plan that allows the individual patients to achieve full depressive episode (Zhao et  al., 2014), although other studies functional recovery in the most effective and efficient manner have found no volumetric differences between first episode (McIntyre et al., 2015; National Institute of Mental Health, 2015 ). patients and healthy controls (McKinnon et  al., 2009; Schmaal The aim of this article is to present recommendations for using et al., 2016). More severe symptoms of depression are associated a patient-centered approach to rapidly provide optimal pharma - with greater hippocampal volume loss (Huang et al., 2013; Taylor cological treatment to patients with MDD. First, we establish the et al., 2014; Elbejjani et al., 2015 ). importance of providing early, optimized treatment of MDD Treatment of depression is generally associated with an based on recent research exploring the effects of depression on increase in hippocampal volume (Schermuly et al., 2011; Huang brain structure and function, using the hippocampus as a well- et al., 2013; Tendolkar et al., 2013) or at least a slowing of volume studied example. Then, we present a consensus of expert opin - loss (Elbejjani et al., 2015), although this has not been observed ion on best practices for physicians to address both depressive in all studies (Schmaal et  al., 2016). Structural changes may symptoms and functional impairment in MDD, with a focus on differ in patients with MDD depending on clinical response to treating with a sense of urgency in the clinical practice setting. treatment. Increased hippocampus volume has also been cor- related with improvement in depressive symptoms: In several cross-sectional studies, hippocampal volume was significantly The Need for Early Optimized Treatment greater in patients who achieved remission from depression Clinicians have historically used a “start low and go slow” compared with nonremitters (Arnone et al., 2013; Nugent et al., 2013). Volume did not differ significantly between remitted MDD approach to pharmacotherapy for MDD, prescribing an initial antidepressant trial for up to 6 to 8 weeks before concluding that patients and healthy individuals (Arnone et  al., 2013; Nugent et  al., 2013; Taylor et  al., 2014). In unmedicated patients with the treatment has failed and an adjustment is warranted (Work Group on Major Depressive Disorder, 2010 ; Qaseem et al., 2008 ). depression, an inverse relation between duration of untreated depression and hippocampal volume has been reported (Arnone However, evidence suggests that MDD should be treated with a greater sense of urgency (Habert et  al., 2016). When depres- et al., 2013). Results of longitudinal studies are mixed; an asso- ciation between improvement in depression and increased sion is not treated with urgency, patient suffering is prolonged. Furthermore, delaying effective treatment may reduce the like- hippocampus volume has been observed in some but not all studies (Schermuly et al., 2011; Arnone et al., 2013; Phillips et al., lihood of both asymptomatic remission and functional recovery, and increase the time to achieve remission (Gormley et al., 1999; 2015). One study found that volumetric changes were associated with cognitive performance at baseline but not with depres- Okuda et  al., 2010; Bukh et  al., 2013; Ghio et  al., 2014). Failure to rapidly and effectively treat major depression may have last- sion severity or improvement (Schermuly et  al., 2011). Volume differences between remitters and nonremitters in some stud- ing effects on patients’ brain structure and function, which may worsen progressively with successive depressive episodes ies appeared to be due at least in part to hippocampal volume loss over time in nonremitters rather than volume recovery in (Moylan et al., 2013). Results of recent brain imagining research provide clear remitted patients (Furtado et al., 2013; Taylor et al., 2014; Phillips et al., 2015). In fact, a smaller hippocampal volume was associ- rationale for treating MDD as rapidly as possible. Untreated MDD is associated with damage to the brain, evident as loss of volume ated with lack of improvement in depression rating scale scores Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 130 | International Journal of Neuropsychopharmacology, 2018 Table 1. Recent Literature on Antidepressant Effects on Hippocampal Volume Deficits Reference Method Comparison Findings Cross-sectional analyses Geerlings et al., MRI ≥65 y; depressed, HC • Smaller volume in depressed (defined by CES-D 2012 score or AD use) vs HC • Smaller volume in AD users vs no AD use (defined as HC) Huang et al., 2013 MRI Treated depressed (AD), • Lower hippocampus, CA1-3, and DG volume in untreated depressed (no depressed vs HC and no AD vs AD AD; 10-pt lower HAM- • AD intermediate betw een no AD and HC for CA1-3 D ), HC Nugent et al., MRI Depressed, remitted, HC • Smaller volume hippocampus and thalamus in 2013 depressed vs remitted and vs HC • Remitted and HC did not differ Arnone et al., MRI Depressed, remitted, HC • V olume reduced in depressed vs remitted and HC; 2013* no difference between remitted and HC Zhao et al., 2014 MRI, meta-analysis Untreated depressed, HC • Smaller volume for depressed vs HC • Smaller volume in subgroup with first episode depression vs HC • No association with number of episodes Travis et al., 2015 MRI Depressed (most taking • Similar volume between groups, but differences in DG AD), HC • Duration of depression was negatively correlated with volume • No association between volume and memory scores Schmaal et al., MRI, meta-analysis Depressed (some taking • Smaller volume for depressed vs HC 2016 AD), HC • No volume difference in patients with first episode depression vs HC; smaller volume in patients with recurrent episodes • No significant effect of AD Longitudinal analyses Schermuly et al., MRI, Depressed, HC • No difference between depressed and HC 2011 4+ mo AD treatment • V olume increased in depressed during treatment; change in volume was associated with baseline function but not depression scores Sheline et al., MRI ≥60 y; depressed, HC • Smaller volume for depressed vs HC at baseline 2012 12 wk sertraline Remitters, nonremitters • Smaller volume predicted poorer MADRS score • Smaller volume in nonremitters vs remitters Husarova et al., MRS Depressed; baseline vs • Myoinositol/creatine and phosphocreatine ratio 2012 7–11 wk escitalopram or postbaseline negatively correlated with MADRS score at baseline venlafaxine (MADRS • Lac/creatine and phosphocreatine ratio, an indicator responders only) of damage or dysfunction, decreased after AD treatment Arnone et al., MRI Depressed, HC • V olume increase after treatment 2013* 8 wk citalopram • No difference between medicated and unmedicated remitters • Significant negative correlation between duration of untreated depression and hippocampal volume Furtado et al., MRI Responders vs • Reduction in volume in nonresponders vs responders 2013 3 mo TMS (some taking AD) nonresponders • No correlation with HAM-D score Tendolkar et al., MRI Depressed; baseline vs • Increased volume after ECT 2013 ECT treatment (TRD; previous posttreatment AD treatment) Godlewska et al., MRI Responders vs • No significant effects 2014 8 wk escitalopram nonresponders • T rend toward normalization of volume in responders Taylor et al., 2014 MRI ≥60 y; depressed, HC • No difference from baseline for HC or remitted 2-y AD treatment (mostly • Volume decrease over time for nonremitters sertraline) • Significantly less volume for nonremitters vs HC at follow up • Worsening or nonimproving MADRS associated with decreasing volume Elbejjani et al., MRI ≥65 y; history of depression • Baseline: smaller volume with greater symptoms in 2015 4 yr AD treatment vs no history women (nonrandomized) • Faster volume loss in women with history of depression vs no history • Slower loss with AD vs no AD in men with history of depression Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Oluboka et al. | 131 Table 1. Continued Reference Method Comparison Findings Phillips et al., MRI TRD; depressed, HC • No difference between depressed and HC at baseline 2015 6–12 mo AD treatment Remitters, nonremitters • Remitters increased in volume, nonremitters decreased Postmortem studies Boldrini et al., IHC; neural progenitor cells Untreated depressed, • More neural progenitor cells and capillary area 2012 capillaries treated depressed (SSRI in individuals treated with SSRIs vs untreated or TCA), NDC depressed and vs NDC • Capillary area, number of progenitor cells, and volume were correlated in treated depressed subjects Boldrini et al., IHC; granule neurons Untreated depressed, • More granule cells in some areas of the DG in 2013 treated depressed (SSRI individuals treated with SSRIs or TCAs; numbers or TCA), NDC were between untreated depressed and NDC • No difference in glia cell numbers Duric et al., 2013 Gene expression; cytoskeletal Depressed, NDC • Dysregulation of pre- and postsynaptic genes in proteins depressed subjects vs NDC Abbreviations: AD, antidepressant; CES-D, Center for Epidemiologic Studies-Depression; DG, denate gyrus; ECT, electroconvulsive therapy; HAM-D , 17-item Hamilton Rating Scale for Depression; HC, healthy control; IHC, immunohistochemistry; MADRS, Montgomery-Åsberg Depression Rating Scale; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NDC, nondepressed control; TCA, tricyclic antidepressant; TMS, transcranial magnetic stimulation; TRD, treatment-resistant depression; SSRI, selective serotonin reuptake inhibitor. *Included both cross-sectional and longitudinal analyses. (Taylor et  al., 2014) and was a significant predictor of poorer depression outcomes (Sheline et al., 2012 ) in patients with late- life depression. The continued presence of depressive symptoms may promote chronic neuronal loss and suppress neurogenesis in the hippocampus (Boldrini et al., 2012, 2013; Duric et al., 2013; Furtado et  al., 2013; Phillips et  al., 2015), and preclinical work (Duman and Aghajanian, 2012; Licznerski and Duman, 2013; Bortolotto et al., 2014) supports the hypothesis that depression may disrupt neural connections in mood-related circuits and provides preliminary evidence that treatment may ameliorate these processes. Evidence from these recent publications suggests that treat- ment may halt and even reverse progressive damage to brain areas associated with depression, underscoring the urgency of rapidly and fully treating depression. Additionally, the duration of untreated illness is a significant predictor of response, remis - sion, and time to remission (Gormley et al., 1999; Okuda et al., 2010; Bukh et al., 2013; Altamura et al., 2015). Related measures such as age at the onset of depression, time since the onset of Figure 1. Early optimized treatment is critical to bringing patients to full symp - tomatic and functional recovery. From ( Habert et al., 2016). depression, duration of the current episode, and the number of previous episodes may also predict treatment outcome (Warden their usual level of functioning, and feeling in emotional con- et  al., 2007; Howland et  al., 2008; Fava et  al., 2009; Seemuller trol….” (Zimmerman et al., 2006). Ultimately, while the remission et  al., 2010; Joel et  al., 2014). Reducing the time between the of symptoms is an important outcome, for patients, recovering onset of depression and optimization of treatment results in from depression implies more than the absence of depressive better short-term clinical outcomes, increases the likelihood of symptoms (Zimmerman et al., 2006). What steps can clinicians achieving full functional recovery (Habert et al., 2016), and, not- take to ensure each patient receives the best possible individu - ably, may reduce the burden of damage to brain areas (Arnone alized care, with no unnecessary delay? The following section et al., 2013; Nugent et al., 2013 ). presents guidance, based of published evidence and the com - To effectively restore a patient to full function, clinicians bined experience of the authors, on providing optimal pharma- must strive to deliver early optimized treatment (Figure  1) cological treatment to patients with MDD, as rapidly as possible. (Habert et  al., 2016). Optimal treatment of depression should address all symptoms and functional impairment, minim- ize antidepressant side effects, address barriers to adherence, How Does the Clinician Provide Early provide strategies for relapse prevention, and elevate patients’ Optimized Treatment for the Individual overall sense of well-being and quality of life (Gelenberg et al.; Patient with MDD? Zimmerman et al., 2012; Kennedy et al., 2016 ; Lam et al., 2016). A patient’s recovery must always be addressed in terms of their Screening and Diagnosis own definition of “well.” Zimmerman and colleagues noted the Identifying MDD patients as early as possible after illness onset primary goal of depression treatment for patients is “presence of positive mental health…feeling their usual self, returning to is an essential first step in optimizing treatment. However, Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 132 | International Journal of Neuropsychopharmacology, 2018 numerous agencies do not recommend routine screening for in those high-risk patients and address symptoms when they depression in adults unless adequate resources and services are are observed (Joffres et  al., 2013; Lam et  al., 2016). For adoles- available for subsequent diagnostic assessment and manage - cents (12–18  years), the US Preventive Services Task Force rec - ment (National Institute for Health and Clinical Excellence, 2009 ; ommends screening when resources are available to ensure an Joffres et  al., 2013; Lam et  al., 2016; Siu et  al., 2016). Concerns accurate MDD diagnosis with appropriate care and follow-up. with screening all adult patients include the lack of robust There is little evidence to support screening patients younger evidence supporting routine screening (due to the paucity of than 12 years of age (US Preventive Services Task Force, 2009). available data on its benefits and harms), the high likelihood An initial screen for depression can be as simple as asking the that patients who screen positive will have been previously 2 questions recommended in the National Institute for Health identified as suffering from depression, and the risk of iden - and Clinical Excellence (NICE) guidelines: “During the last month, tifying very mild depression that does not require treatment have you often been bothered by feeling down, depressed, or (Joffres et al., 2013; Keshavarz et al., 2013; O’Connor et al., 2016). hopeless? During the last month, have you often been bothered However, the assertion that mild depression does not require by having little interest or pleasure in doing things?” A  more treatment may not consider the possibility that an individual in-depth assessment using a validated instrument should fol- may have mild depressive symptoms related to a resolving (but low, if there is an affirmative response to either question. Given not yet resolved) depressive episode or may be experiencing the that no biological markers have been established for depression onset of an impending, more severe depressive episode. Other (Huang and Lin, 2015), objective screening questionnaires are subgroups of people in this mildly depressed population may critical tools to employ when assessing a depressed patient. Just include those individuals with chronically lower hedonic tone, as diabetes or hypertension would not be diagnosed without who could be more susceptible to develop either a major depres- blood glucose levels or blood pressure assessments, a diagnosis sive episode or what is described in the DSM-5 as dysthymia (or of MDD requires the measurement of symptoms and associated persistent depressive disorder) (Sternat et al., 2014; Sternat and functional impairment (American Psychiatric Association, 2013). Katzman, 2016). A number of validated assessment tools that incorporate MDD Still, the literature at present suggests that routine screen- diagnostic criteria are available, including both symptom scales ing is not recommended; rather, clinicians should consider and functional assessments ( Table  2). The authors recommend screening patients with risk factors for depression, as outlined the use of the 9-item Patient Heath Questionnaire (PHQ-9), a in Box 1 (National Institure for Health and Clinical Excellence, brief, self-administered assessment incorporating DSM diag- 2009; Lam et al., 2016), or be alert to the possibility of depression nostic criteria that patients can complete quickly and that may Box 1. Depression Screening in Primary and Secondary Care Settings CANMAT guidelines recommend screening patients with risk factors for depression (Lam et al., 2016): Clinical Risk Factors Symptom Risk Factors History of depression Unexplained physical symptoms Family history of depression Chronic pain Psychosocial adversity Fatigue High users of the medical system Insomnia Chronic medical conditions (especially cardiovascular Anxiety disease, diabetes, and neurological disorders) Substance abuse Other psychiatric conditions Times of hormonal challenge (e.g., peripartum) Screening A 2-question screen can be used for identifying patients that may require more detailed assessment (National Institute for Health and Clinical Excellence, 2009 ) 1. In the last month, have you been bothered by little interest or pleasure in doing things? 2. In the last month, have you been feeling down, depressed or hopeless? Patients who respond “yes” to either of these questions should be assessed with an instrument such as the PHQ (National Institute for Health and Clinical Excellence, 2009 ; Patient Health Questionnaire, 1999; Lam et al., 2016) Over the past 2 weeks, how often have you been bothered by any of the following problems, scored 0 (not at all) to 3 (nearly every day)? 1. Little interest or pleasure in doing things 2. Feeling down, depressed, or hopeless 3. Trouble falling asleep, staying asleep, or sleeping too much 4. Feeling tired or having little energy 5. Poor appetite or overeating 6. Feeling bad about yourself or that you’re a failure or have let yourself or your family down 7. Trouble concentrating on things, such as reading the newspaper or watching television 8. Moving or speaking so slowly that other people could have noticed. Or, the opposite - being so fidgety or restless that you have been moving around a lot more than usual 9. Thoughts that you would be better off dead or of hurting yourself in some way Abbreviation: CANMAT, Canadian Network for Mood and Anxiety Treatments. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Oluboka et al. | 133 Table 2. Screening/Monitoring Tools for the Clinic (Endicott and Dorries, 2009; Lam et al., 2016) Instrument Structure Reference Symptoms Patient Health Questionnaire 9 items, each scored 0–3 Kroenke and Spitzer, 2002 Quick Inventory for Depressive Symptomatology, 16 items, each scored 0–3 Rush et al., 2003 Self-Rated Clinically Useful Depression Outcome Scale 18 items, each scored 0–4 Zimmerman et al., 2008 Behavior and Symptom Identification Scale 32 items, each scored 0–4 Eisen et al., 1994 ) (BASIS-32) Function/quality of life Sheehan Disability Scale 3 items, each scored 0–10 Sheehan et al., 1996 World Health Organization Disability 36 items in 6 domains, each scored 1–5 Posl et al., 2007 Assessment Schedule II Lam Employment Absence and Productivity Scale 10 items, 3 open response and 7 scored on a 5-point, Lam et al., 2009) Likert scale Social Adjustment Scale, Self-Report Version 48 items in 6 domains, each rated on a 5-point, Likert Weissman and Bothwell, 1976 scale Social and Occupational Functioning Assessment Single scale, scored 0–100 Rybarczyk, 2011 Scale EuroQoL-5D Single scale, scored 0–100 EuroQoL, 1990 be administered repeatedly to monitor symptom response to obsessive-compulsive disorder, posttraumatic stress disorder, treatment (Kroenke and Spitzer, 2002). For a definitive diagnosis, or bipolar disorder, when a patient presents with depression the use of any assessment tools should always be coupled with commonly results in treatment-resistance because the comor- a clinician’s good judgement, a psychiatric interview, and add- bid condition is inappropriately or inadequately treated. When itional assessments to rule out other disorders ( Lam et al., 2016). clinicians understand which conditions may be associated Assessment tools also provide the clinician with a measure with a higher risk of MDD (e.g., substance abuse, low hedonic of the severity of specific depression symptoms or the degree tone, or attention deficit hyperactivity disorder [ADHD]; Kessler of functional impairment. Determining both the episode speci- et  al., 2003; Sternat et  al., 2014), they are better able to remain fiers and the severity of depression at diagnosis is critical to alert for signs of depression in patients with those conditions developing an appropriate treatment plan and establishing (Epstein et  al., 2014). An undiagnosed medical or psychiatric baseline measurements to monitor improvement during treat - comorbidity can interfere with response to MDD treatment ment (Kennedy et  al., 2016 ; Lam et  al., 2016). However, criteria (McIntyre et  al., 2015; Bron et  al., 2016). The 2015 Florida Best for depression severity provided by various guidelines are not Practice Psychotherapeutic Medication Guidelines for Adults consistent (Davidson, 2010). The DSM-5 and the International recommends differential screening for psychiatric and medical Classification of Diseases, Tenth Revision ( American Academy comorbidities (Florida Agency for Health Care Administration, of Professional Coders, 2013) (ICD-10) definitions for depression 2015), which is in line with the approach set forth by the severity differ based on the threshold numbers of symptoms National Institute of Mental Health. The National Institute of present during a depressive episode, intensity of symptoms, and Mental Health recommends the progression to more patient- the resulting impairments/disability (Davidson, 2010). Although centered diagnostic approaches that consider an individual’s the criteria are similar, a patient meeting the ICD-10 criteria for genetic, physiologic, and behavioral profiles to achieve a specific mild depression, for example, might have subthreshold depres- and informative diagnosis (National Institute of Mental Health, sion based on DSM-5 criteria (Davidson, 2010). The DSM-5 and 2015). Although subsets of patients with an increased risk for ICD-10 criteria for severity include both number of symptoms MDD have been noted (Box 1) ( National Institute for Health and and degree of impairment or disability (Davidson, 2010) The Clinical Excellence, 2009 ; Lam et  al., 2016), risk factors serve American Psychiatric Association, the British Association for only as a guide. Ultimately, the clinician must determine which Psychopharmacology, NICE, and CANMAT recommendations individual patients require additional screening for an MDD define MDD severity according to DSM criteria only ( Work diagnosis. Group on Major Depressive Disorder, 2010 ; Anderson et  al., 2008; National Instutute for Health and Clinical Excellence, Individualized Treatment Plan 2009; Bauer et  al., 2013; MacQueen et  al., 2016 ). CANMAT and The development of an individualized treatment plan includes American Psychiatric Association guidelines address psychia- identifying specific treatment goals and determining the best trists; NICE and British Association for Psychopharmacology strategies to employ to accomplish these goals ( Lam et al., 2016). guidelines address both specialists and primary care physicians. The ideal treatment plan takes into account the patient’s spe - Finally, because medical comorbidities can complicate cific array of symptoms and associated functional impairment, depression screening and diagnosis, clinicians should be aware together with the medical and lifestyle characteristics that of their role in both under- or misdiagnosis of MDD ( Huerta- might contribute to the success or failure of a given treatment, Ramirez et al., 2013; McGuire et al., 2014). Depression symptoms as outlined by the RDoC Initiative for developing new treat- may be missed in patients presenting with symptoms of comor- ments. The RDoC Initiative recommended treatment be based bid conditions, resulting in delayed diagnosis and treatment on individual patient characteristics, personal and medical (McGuire et al., 2014; Lam et al., 2016; Thase, 2016). Likewise, not history, and quality of life (National Institute of Mental Health, ruling out the presence of another psychiatric disorder, such as Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 134 | International Journal of Neuropsychopharmacology, 2018 2015). An individual patient’s treatment goals should encom- outcomes (Ashton et al., 2005; Cameron et al., 2014; Culpepper pass the concept of “treating-to-target”—treating the patient to et al., 2015). achieve the goal of full and sustained functional recovery across all aspects of MDD (McIntyre et  al., 2015). A  treating-to-target Antidepressant Treatment Selection approach includes asymptomatic remission, but also functional A key factor in achieving treat-to-target goals is the selection of recovery, including improvement in social, interpersonal, work, a treatment best matched to the individual patient. Rapid treat- and family domains. It is essential to consider that a patient’s ment optimization requires that antidepressant drug and dose concept of wellness may differ substantially from that of the selection is based on patients’ individual clinical characteristics treating physician (Zimmerman et  al., 2006; McIntyre et  al., rather than a habit-based, “one-size fits all” approach ( National 2015), and ultimately, it is the patient’s concept that is the most Institute of Mental Health, 2015 ; Habert et  al., 2016). To date, important treatment goal. pharmacogenetics/genomic biomarkers have yet to demon- A collaborative approach to developing and following the strate a positive impact on health outcomes in clinical practice; treatment plan is needed to achieve treating-to-target goals. however, future research may eventually prove biomarkers to be The physician and patient should decide together how best to beneficial in selecting appropriate antidepressants in specific address bothersome symptoms and return the patient to pre- patient populations (Dunlop and Mayberg, 2014; Leuchter et al., illness functioning. The treatment team may also include family 2014; Thase, 2014a). Some evidence indicates that antidepres - members, other clinicians (nurses, social workers, specialists), sant efficacy or tolerability may vary based on patient genotype. and those involved in other aspects of recovery, for instance For example, in clinical trials of venlafaxine (extended release addiction counselors (Work Group on Major Depressive Disorder, or immediate release), the cytochrome P450 (CYP) 2D6 poor 2010; Lam et al., 2016). This approach yields a more comprehen- metabolizer genotype is associated with significantly smaller sive MDD treatment plan and might also improve outcomes for mean improvements in depressive symptoms and significantly comorbid conditions (Teh et al., 2010 ; Jiang et al., 2011). lower rates of remission vs those with the extensive metabolizer Treatment plans often evolve over time, as patients pro- phenotype (Lobello et  al., 2010). In depressed patients admin- gress or encounter obstacles to recovery ( McIntyre et al., 2015). istered escitalopram, CYP2D6 genotypes yielding more rapid Given that about one-half of patients who initiate an anti - metabolism were significantly associated with a slower time depressant will fail to achieve remission (Thase et  al., 2005 ; to remission, and CYP2C19 poor metabolizers had significantly Machado et al., 2006; Thase et al., 2007 ), several treatment steps higher serum escitalopram levels compared with extensive may be needed to achieve successful outcomes. Treatment fail - metabolizers (Tsai et  al., 2010). Plasma vortioxetine levels are ures may result from the lack of treatment efficacy, noncompli - reported to be twice as high in CYP2D6 poor metabolizers com- ance, or poor tolerability. An effective treatment plan adjusts pared with CYP2D6 extensive metabolizers (Zhang et al., 2015). to address these obstacles to optimize treatment as rapidly as These findings suggest that certain patients may require thera - possible (Culpepper et al., 2015; Habert et al., 2016). For patients peutic drug monitoring and/or dose adjustment for efficacy or with MDD who do not respond to an initial treatment, phy- safety if antidepressant drugs whose exposure or efficacy vary sicians may consider increasing the dose, adding adjunctive with metabolizer genotype are prescribed (Probst-Schendzielorz treatment, or switching to an antidepressant with a differ - et al., 2015; Zhang et al., 2015). ent mechanism of action (Kennedy et al., 2016 ). However, evi- In the absence of reliable biomarkers, before selecting an dence suggests that outcomes are less robust for patients who antidepressant, all relevant clinical factors that may be asso- require subsequent treatment steps or when changes to an ciated with differences in drug efficacy should be considered. effective treatment are delayed. Remission rates for patients Such factors include age, illness severity, predominant symp- in 4 successive treatment steps in the Sequenced Treatment toms (e.g., agitation vs retardation), comorbidities, areas of Alternatives to Relieve Depression trial dropped progressively, functional impairment, and previous antidepressant treat - from 37% at step 1 to 13% at step 4 (Rush et al., 2006b). Patients ment history (Uher et  al., 2012; Kennedy et  al., 2016). While who remitted during the first treatment step experienced antidepressants may be similar in efficacy overall ( Work Group greater improvements in function compared with patients who on Major Depressive Disorder, 2010 ; Gartlehner et  al., 2011; remitted at step 2 (Trivedi et al., 2013). Providing a longer treat - Schueler et  al., 2011), published literature suggests there may ment trial (8 weeks vs 4 weeks) before switching is associated be potential benefits of some drugs in individuals with specific with poorer functional outcomes, even among patients who symptoms or comorbid conditions (Sternat and Katzman, 2016). remit on the second treatment (Romera et al., 2012). Research The CANMAT guidelines include recommendations for specific examining early response to antidepressant treatment sug- antidepressant drugs or classes based on clinical specifiers and gests that treatment adjustment can be considered after just dimensions of MDD, although the evidence is not of the highest 2 to 4 weeks of treatment (Habert et  al., 2016; Kennedy et  al., quality (Kennedy et  al., 2016). Analysis of antidepressant effi - 2016). Taken together, these findings suggest that developing cacy in patient subpopulations has not been published for all a plan that is focused on early optimization of treatment, with antidepressant drugs, and understanding effectiveness of treat- continued measurement-based follow-up to ensure the patient ment among individuals with specific demographic, medical, is progressing, is a critical step in bringing the patient to full or genetic characteristics remains an important research goal functional recovery. (National Institute of Mental Health, 2015 ). A successful treatment plan also includes patient education Characteristics that may affect treatment tolerability or regarding therapy options, possible associated adverse effects, adherence for individual patients are also important considera - and the expected course of recovery. A patient who knows what tions. These include past response, potential sensitivity to side to expect from an antidepressant treatment comprehends effects, family history, potential for drug-drug interactions, sim - when and why treatment adjustments might occur and under - plicity of use, issues associated with abrupt discontinuation, stands the value of long-term antidepressant treatment is more cost, and branded vs generic formulations ( Kennedy et al., 2016 ). likely to be adherent to the treatment plan and achieve positive Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Oluboka et al. | 135 Tolerability and compliance can be important differentiators In the majority of studies, improvement was defined as a per - when it is not clear that one antidepressant drug or class may centage change in depression scale scores from baseline (often hold an efficacy advantage for a particular patient ( Kennedy ≥20% change) assessed at 1 to 4 weeks after treatment initiation. et  al., 2016). Although adverse events are associated with all Importantly, lack of early improvement (negative predictive drugs, specific antidepressants are associated with higher rates value) appears to be a more accurate predictor of eventual treat - of particularly troublesome side effects, such as weight gain and ment outcome than is achieving early improvement (positive sexual dysfunction (Ashton et al., 2005; Serretti and Chiesa, 2009; predictive value) (Habert et  al., 2016). These data suggest that Serretti and Mandelli, 2010; Clayton et al., 2014). Tolerability con- in clinical practice, physicians can use a lack of improvement cerns are heightened for patients who have comorbid condi- early in treatment as an indicator that modification of therapy tions that could be worsened by antidepressant effects, or who is needed. take concomitant medications likely to contribute to drug-drug Most studies examining the predictive value of early interactions (Manolopoulos et  al., 2012; Kennedy et  al., 2016 ; improvement used a 2-week time point to assess early treat- Thase et al., 2016). Efficacy and tolerability differences between ment response (Habert et al., 2016). Although 2 weeks is not an drugs must be balanced based on the needs of the individual adequate trial for efficacy, information from the first week or patient (Gartlehner et al., 2005; Machado et al., 2006; Gartlehner two can be useful for making dose adjustments (Kennedy et al., et al., 2008a, 2008b; Cipriani et al., 2009). 2016). Given that increases of 2 to 3 times an initial dose are Physicians may also consider the importance of prescription common, delaying dose adjustments results in patients being insurance coverage when selecting an antidepressant treat- under-dosed and increases time to recovery (Mohr et al., 2015). ment for a specific patient. A recent report suggests that most Baseline and weekly assessments of both depressive symptoms US healthcare plans implement restriction strategies other than and functioning are therefore recommended (Szegedi et  al., complete exclusion (e.g., tier placement, administrative restric- 2009; Lam et al., 2011). tions) to manage the cost and utilization of newer antidepres- The CANMAT algorithm for managing inadequate anti- sant treatments (Hodgkin et al., 2015). Most older, less expensive depressant response states that a dose increase should be the agents are unrestricted. The selection of branded vs generic first step in optimizing treatment and recommends considering medications should be considered. Generic medications provide a switch or addition of adjunctive treatment after 2 to 4 weeks a lower cost option. However, even though approval of a generic if no improvement is noted with a dose adjustment, or a dose medication requires a demonstration of bioequivalence, which increase is not tolerated (Kennedy et  al., 2016 ). As with initial does sometimes fail ( Chenu et al., 2009 ; Woodcock et al., 2012), decisions regarding treatment choice, a range of clinical fac- there nonetheless may be efficacy or tolerability differences for tors should be considered in determining a second treatment some patients taking generic drugs, possibly related to differ- step (Table  3) (Kennedy et  al., 2016 ). Switching to a new anti- ence in excipients ( Gallelli et al., 2013 ; Andrade, 2015). Discussing depressant may be appropriate when the initial drug has poor insurance coverage may inform antidepressant selection, as tolerability or when a patient prefers a simpler regimen with a restrictions and higher copay requirements may preclude single medication. An adjunctive medication can complement patients from following through with their prescription. the initial antidepressant drug, targeting specific side effects A review of nonpharmacological interventions is beyond the and residual symptoms when there is a partial response, while scope of this article; however, it is important to note that psy- giving the first drug a longer trial ( Cameron et al., 2014; Kennedy chological therapies are recommended as first-line treatment or et al., 2016). as an adjunctive to pharmacological therapy for some patients Table  3. Factors to Consider in Choosing Between Switching to (Parikh et al., 2016). Complementary and alternative medicines Another Antidepressant Monotherapy or Adding an Adjunctive have proven beneficial for some patients with MDD, particularly Medication (Level 3 Evidence) those with mild to moderate depression, or as adjunctive treat- ment in patients with moderate to severe depression (Ravindran Consider switching to another antidepressant when: et al., 2016). As full functional recovery is all too commonly not It is the first antidepressant trial. achieved with pharmacological treatment alone, consideration There are poorly tolerated side effects to the initial of nonpharmacological interventions may prove essential to antidepressant. achieving optimized treatment (McIntyre et al., 2015). There is no response (<25% improvement) to the initial antidepressant. There is more time to wait for a response (less severe, less Assessment of Early Improvement for Early functional impairment). Optimized Treatment Patient prefers to switch to another antidepressant. Consider an adjunctive medication when: Once an initial antidepressant selection is made, physicians There have been 2 or more antidepressant trials. should be thorough and persistent in monitoring patient The initial antidepressant is well tolerated. response through clinical interviews and by using validated There is partial response (>25% improvement) to the initial measurement tools (Papakostas, 2016). Maintaining initial antidepressant. treatment for up to 8 weeks (Work Group on Major Depressive There are specific residual symptoms or side effects to the initial Disorder, 2010) before making adjustments is outdated. Instead, antidepressant that can be targeted. clinicians must shift to evidence-based and patient-specific There is less time to wait for a response (more severe, more prescribing with rapid optimization of treatment, closely moni - functional impairment). toring efficacy and tolerability over the first 1 to 4 weeks of Patient prefers to add on another medication. treatment to heighten adherence and reduce time spent on inef - fective medication ( Habert et al., 2016; Lam et al., 2016). With permission from (Kennedy et al., 2016 ). A growing body of research has demonstrated that early For the initial antidepressant trial. In subsequent trials, lack of response (<25% improvements in depressive symptoms and functioning predict improvement) may not be a factor for choosing between switch and adjunctive eventual remission or recovery (reviewed in Habert et al., 2016). strategies. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 136 | International Journal of Neuropsychopharmacology, 2018 Measurement-based care requires the use of validated tools gain, sexual dysfunction, failure of patients to perceive bene- for monitoring early improvement in symptoms and func - fits of treatment, and premature discontinuation of treatment tion (Lam et  al., 2016), and numerous tools are available for after symptoms have improved (Masand, 2003; Ashton et  al., the clinical setting ( Table  2). Symptom assessments used in 2005; Burra et al., 2007; Fortney et al., 2011). Clinical experience clinical trials (17-item Hamilton Rating Scale for Depression, has shown that patients are reluctant to start another anti - Montgomery–Åsberg Depression Rating Scale) are too time-con- depressant following a long trial of an ineffective antidepres- suming and burdensome for application in daily clinical prac- sant. Compliance with the second antidepressant may also be tice. Guideline-based validated instruments such as the PHQ-9 compromised if a patient mistakes withdrawal symptoms from or Quick Inventory of Depressive Symptomatology, in contrast, the previous medication for side effects of the new one. Using a are fast, easy, and self-administered (Kroenke and Spitzer, 2002; crossover technique to taper one antidepressant while initiating Rush et al., 2006a; Thase, 2014b). a new one may reduce or eliminate discontinuation symptoms Because treatment goals include a full functional recov- (Masand, 2005). SwitchRx.ca offers suggested crossover sched- ery and return to premorbid quality of life, improvements in ules for antidepressant switches (Canadian Network for Mood functional impairment should also be monitored (Lam et  al., and Anxiety Treatments, 2017). 2016). The Sheehan Disability Scale is a useful tool for identify - To prevent early discontinuation and optimize patient adher- ing functional impairment and severity of functional disability ence to treatment, physicians should choose antidepressants (Sheehan, 2000 ; Sheehan and Sheehan, 2008 ). Similarly, various with improved tolerability profiles, use the fewest medications patient-administered scales are available for evaluating quality possible, and adjust dosages/treatment to minimize adverse of life (Endicott and Dorries, 2009; Lam et al., 2016). Improvement effects (Cameron et al., 2014; Culpepper et al., 2015). Data from in function and quality of life often lags behind symptom remis- the Medical Expenditure Panel Survey for 1996 to 2001 showed sion in patients with MDD (Bech, 2005; Sheehan and Sheehan, that >40% of patients treated for a first depressive episode dis - 2008; IsHak et al., 2011). Similar to symptom improvement, func- continued antidepressant treatment within the first 30  days tional improvement in the first 2 weeks of treatment is predict - (Olfson et al., 2006). Poor tolerability was identified as a primary ive of functional outcomes (Soares et al., 2014b), indicating that reason for noncompliance (Demyttenaere et al., 2001). In a sur- weekly assessment of function and quality of life can be valu - vey of 350 adults with MDD, adverse events were the second- able for considering adjustments to the treatment plan. Other most common cause of discontinuing an antidepressant (after specialized outcome scales may be needed to screen for comor- lack of efficacy) and second-most common reason for noncom - bid conditions, both at initial assessment and when adjusting pliance (after forgetting to take medication) (Ashton et al., 2005). the treatment plan in the case of treatment failure. Because Weight gain, sexual dysfunction, and fatigue/lack of energy were patients with MDD have a 2-fold higher prevalence of ADHD the most troublesome side effects and among the most likely to relative to the general population and the presence and sever- result in noncompliance or treatment discontinuation (Ashton ity of comorbid ADHD can inform treatment selection for both et  al., 2005). Physicians should closely monitor antidepressant conditions (Canadian Attention Deficit Hyperactivity Disorder tolerability, including the most common and most trouble- Resource Alliance, 2011; Bond et  al., 2012), the authors recom- some side effects for the prescribed drug or class, utilizing dose mend assessing for ADHD using the Adult ADHD Self-Report adjustment, pharmacological or nonpharmacological treatment Scale (Kessler et  al., 2005) in patients with treatment-resistant of the adverse effect, or switching to a different drug to mitigate depression. the impact on compliance ( Anderson et al., 2008; Work Group on In addition to in-office assessments, internet-based tools Major Depressive Disorder, 2010 ). allow patients to monitor depressive symptoms and functional Additional steps to optimize patient adherence may involve impairment between office visits. One such tool is MoodFx, an patient education, setting realistic patient expectations, employ - interactive website focusing on depression and anxiety (Work ing collaborative care systems, and providing adequate follow- With Us Program, 2014; Mohr et  al., 2015; MoodFX website, up care (Cameron et  al., 2014; Culpepper et  al., 2015). Patients 2016). Web-based tools allow patients to monitor their symp- who are closely monitored by their healthcare providers have toms, cognitive deficits, and workplace functioning using vali - higher rates of treatment adherence. Physicians can maintain dated questionnaires (PHQ-9, the Generalized Anxiety Disorder patient communication via regular office visits or augment Questionnaire-7, the Lam Employment Absence and Productivity scheduled appointments using internet-based tools such as Scale, the Perceived Deficits Questionnaire-5, and items on gen - MoodFx (Work With Us Program, 2014) or MedLink ( Mohr et al., eral functioning and quality of life from the Clinically Useful 2015). Tools for assisting the physician in monitoring adher - Depression Outcome Scale). Patients can monitor improvement ence include electronic monitoring, pill counts, blister-packing and share results with their clinician, which supports their medications, medication diaries, patient self-reporting, chart ongoing engagement in the treatment process. reviews, easy availability of prescription renewal, and phar - macy records (Osterberg and Blaschke, 2005; Velligan et al., 2006 ; Byerly et al., 2007; Nakonezny et al., 2008 ; van Onzenoort et al., Treatment Adherence 2012; Faurholt-Jepsen et al., 2014; Sutton et al., 2014; Orrell et al., Medication adherence is critical to achieving full, functional 2015). recovery and is one of the major challenges hindering opti- mal treatment of MDD (Kohler et al., 2012; Ho et al., 2015; Lam Long-Term Treatment Plan et  al., 2016). Lack of adherence to antidepressant treatment is associated with poor treatment outcomes, including a greater Patients benefit from understanding the chronic nature of MDD risk of relapse (Gopinath et  al., 2007), increased impairments and the need for a long-term plan to ensure they return to pre- in functioning (Burton et  al., 2007), and greater risk of suicide illness functioning and lessen the risk of relapse or recurrence. (Ruengorn et  al., 2012). Obstacles to adherence include poor Clinical evidence supports maintenance treatment of MDD with tolerability, social stigma, inadequate patient education, low pharmacotherapy, psychotherapy, and other non-pharmaco - motivation, medication cost, delayed onset of efficacy, weight therapies (Moller, 2008; Glue et  al., 2010 ; Lam et  al., 2016). The Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Oluboka et al. | 137 expected duration of antidepressant treatment should be dis- Clarke et al., 2015; Lam et al., 2016). CANMAT recommends cog- cussed, and patients should be made aware of medication side nitive behavioral therapy as a first-line maintenance treatment effects that may occur later in treatment as well as possible dis- for depression (Parikh et al., 2016). The long-term treatment plan continuation symptoms. Long-term maintenance pharmaco- must be individualized to each patient and evolve as the patient therapy should be considered for patients who have risk factors progresses through treatment ( McIntyre et al., 2015). for recurrence of depression ( Work Group on Major Depressive Disorder, 2010; Lam et al., 2016). Nonpharmacological interven- Conclusions tions for MDD, including psychotherapy, behavior modification, and implementation of positive lifestyle habits (i.e., physical Recent studies suggest that delaying the treatment of MDD fitness, nutrition, weight loss, stress reduction/tolerability exer - can result in progressive damage to brain areas associated cises, establishing a strong social network), may have long-term with depression and that pharmacotherapy may halt and even benefits, including mitigation of recurrence ( Houle et  al., 2013 ; reverse those effects, underscoring the importance of rapidly Box 2. Q and A When do you screen for depression, and what tools do you use? • Consider screening patients with risk factors for depression, or be alert to the possibility of depression in high-risk patients, following up when clinical symptoms are noted (Joffres et al., 2013; Lam et al., 2016) • A positive response on an initial 2-question screen (“During the last month, have you often been bothered by feeling down, depressed or hopeless? During the last month, have you often been bothered by having little interest or pleasure in doing things?”) can be followed up using the PHQ-9 ( Kroenke and Spitzer, 2002) How do you determine treatment goals for an individual patient? • An individual patient’s treatment goals focus on full and sustained functional recovery across all aspects of MDD (McIntyre et al., 2015). The goal should include symptomatic remission, but also functional recovery, including societal, interpersonal, work, and family domains, and any other health outcomes defined by the individual patient and/or clinician ( Zimmerman et al., 2006; McIntyre et al., 2015). • The patient’ s concept of remission may differ from that of the treating physician (Zimmerman et al., 2006). What factors do you consider in selecting an antidepressant? • The indi vidual patient’s diagnostic specifiers, symptoms and severity, areas of impairment, other clinical characteristics, and medical history together with patient biases and preferences for treatment should be considered when choosing an antidepressant (National Institute of Mental Health, 2015 ; Habert et al., 2016; Kennedy et al., 2016 ). • A range of factors (age, gender, MDD severity, predominant symptoms, diagnostic subtype, and comorbidities) could be associated with differences in efficacy or tolerability for specific drugs or classes ( Uher et al., 2012; Kennedy et al., 2016 ). What baseline assessments (for symptoms and function) do you use? How do you assess progress during treatment? What scales do you use? • The PHQ-9 and SDS ar e brief, validated scales that can be used to measure baseline symptoms of depression and functional impairment, respectively (Kroenke and Spitzer, 2002). • The same instruments can be administer ed weekly during acute treatment to assess changes in symptoms and function during treatment. • Patients can also monitor changes in symptoms and share results and concerns with their clinician via mobile device applications (Mood Disorders Society of Canada 2014; Mohr et al., 2015). How early do you optimize the treatment step when needed? • Early improvements in depressive symptoms and in functioning, measured 1 to 4 weeks after initiation of treatment, predict later remission or recovery ( Koran et al., 1995; Szegedi et al., 2003 ; Henkel et al., 2009 ; Kok et al., 2009; Szegedi et al., 2009 ; Lin et al., 2011; Joel et al., 2014 ; Lam et al., 2014; Soares et al., 2014a) • Information from the first week or 2 of treatment can be useful for making dose adjustments ( Kennedy et al., 2016 ); a switch to another antidepressant or addition of adjunctive treatment should be considered after 2 to 4 weeks if no improvement is noted with a dose adjustment or if the patient does not tolerate the dose increase (Kennedy et al., 2016 ). What are the major obstacles to adherence? How do you monitor for adherence? • Obstacles to adherence include poor tolerability, social stigma, inadequate patient education, lack of patient motivation, concerns about medication cost, weight gain, sexual dysfunction, delayed onset of efficacy, failure of patients to perceive benefits of treatment, and premature discontinuation of treatment after symptoms have improved ( Masand, 2003; Ashton et al., 2005; Burra et al., 2007; Fortney et al., 2011) • T ools for monitoring adherence to antidepressant medication include electronic monitoring, pill counts, medication diaries, patient self-reporting, chart reviews, prescription renewal, and pharmacy records ( Osterberg and Blaschke, 2005; Velligan et al., 2006; Byerly et al., 2007; Nakonezny et al., 2008 ; Faurholt-Jepsen et al., 2014; Sutton et al., 2014; Orrell et al., 2015). How do comorbid conditions (psychiatric or general medical) affect a long-term treatment plan? • Because the presence of comorbid psychopathologies is a risk factor for recurrence of depression, long-term treatment is recommended for patients with comorbid conditions (Lam et al., 2016). • T reatment efficacy for both antidepressant and psychological treatments may vary with medical of psychiatric comorbidities, so these should be taken into account when developing a long-term treatment plan ( Kennedy et al., 2016 ; Parikh et al., 2016). • The long-term tr eatment plan should also include addressing comorbid conditions in the maintenance period (Lam et al., 2016). Abbreviations: MDD, major depressive disorder; PHQ-9, 9-item Patient Health Questionnaire; SDS, Sheehan Disability Scale. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 138 | International Journal of Neuropsychopharmacology, 2018 treating depression to full recovery. Our recommendations for Eli Lilly, Euthymics, Janssen, Lundbeck, Merck, Otsuka, Pfizer, delivering rapidly optimized care are summarized in Box 2.  Pierre Fabre, Servier, Shire, Takeda, and Valeant. Early optimized treatment of MDD, using measurement-based care, and customizing treatment to the individual patient may References afford the best possible outcomes for each patient and increase the likelihood they will achieve full functional recovery. Using a Altamura AC, Serati M, Buoli M (2015) Is duration of illness really patient-centered approach throughout MDD treatment entails influencing outcome in major psychoses? Nord J Psychiatry aligning the treatment plan with each patient’s individual char- 69:1–15. acteristics and preferences and expectations for treatment, American Academy of Professional Coders (2013) ICD-10 including, most critically, their own definition of wellness and resource: coding for major depressive disorder.http://cloud. goals for recovery. aapc.com/documents/Depressive-Disorder-ICD-10-BH.pdf. American Psychiatric Association (2013) Major depressive dis - order. In: Diagnostic and statistical manual of mental disor - Acknowledgments ders (DSM-5), 5th ed, pp160–168. Washington, DC: American This review was supported by Pfizer Canada Inc. Medical writing Psychiatric Association. Anderson IM, Ferrier IN, Baldwin RC, Cowen PJ, Howard L, Lewis support was provided by Kathleen Dorries at Peloton Advantage and was funded by Pfizer. 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Dr. Katzman has received grant support, Ashton AK, Jamerson BD, W LW, Wagoner C (2005) Antidepressant- participated in advisory boards, and/or received honoraria for related adverse effects impacting treatment compliance: lectures from the Canadian Foundation for Innovation, Lotte results of a patient survey. Curr Ther Res Clin Exp 66:96–106. & John Hecht Memorial Foundation, Allergan, AstraZeneca, Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Moller HJ Bedrocan, Biotics, Bristol-Myers Squibb, Eli Lilly, Genuine (2013) World Federation of Societies of Biological Psychiatry Health, Janssen, Lundbeck, Merck, Otsuka, Pfizer, Purdue, (WFSBP) guidelines for biological treatment of unipolar Shire, Sunovion, and Tweed. Dr. Habert has served on advis - depressive disorders, part 1: update 2013 on the acute and ory boards and as a speaker or consultant for Pfizer, Amgen, continuation treatment of unipolar depressive disorders. 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Dr. Boldrini M, Santiago AN, Hen R, Dwork AJ, Rosoklija GB, Tamir H, Milev has served on advisory boards or similar committees for Arango V, John Mann J (2013) Hippocampal granule neuron AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Lundbeck, number and dentate gyrus volume in antidepressant-treated Otsuka, Pfizer, Servier, and Shire; has participated in clinical and untreated major depression. Neuropsychopharmacology trials or studies for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, 38:1068–1077. Lundbeck, Brain Cells, and Pfizer; has received honoraria or other Bond DJ, Hadjipavlou G, Lam RW, McIntyre RS, Beaulieu S, fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Lundbeck, Schaffer A, Weiss M (2012) The Canadian Network for Mood Otsuka, Pfizer, and Sunovion; and has received research grants and Anxiety Treatments (CANMAT) task force recommenda- from CIHR, OMHF, OPGRS, OBI, and CANBIND. 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Compr Boerescu DA, Rahgeb M (2012) Why do some depressed out- Psychiatry 49:131–140. patients who are in remission according to the Hamilton Zimmerman M, McGlinchey JB, Posternak MA, Friedman M, Depression Rating Scale not consider themselves to be in Attiullah N, Boerescu D (2006) How should remission from remission? J Clin Psychiatry 73:790–795. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Neuropsychopharmacology Oxford University Press

Functional Recovery in Major Depressive Disorder: Providing Early Optimal Treatment for the Individual Patient

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Abstract

Major depressive disorder is an often chronic and recurring illness. Left untreated, major depressive disorder may result in progressive alterations in brain morphometry and circuit function. Recent findings, however, suggest that pharmacotherapy may halt and possibly reverse those effects. These findings, together with evidence that a delay in treatment is associated with poorer clinical outcomes, underscore the urgency of rapidly treating depression to full recovery. Early optimized treatment, using measurement-based care and customizing treatment to the individual patient, may afford the best possible outcomes for each patient. The aim of this article is to present recommendations for using a patient-centered approach to rapidly provide optimal pharmacological treatment to patients with major depressive disorder. Offering major depressive disorder treatment determined by individual patient characteristics (e.g., predominant symptoms, medical history, comorbidities), patient preferences and expectations, and, critically, their own definition of wellness provides the best opportunity for full functional recovery. Keywords: depression, function, pharmacotherapy, treatment optimization Introduction Major depressive disorder (MDD) is the leading cause of disabil- symptoms, individuals with MDD experience impairments in ity worldwide, affecting an estimated 350 million individuals physical, occupational, and social functioning (Kessler et  al., globally (World Health Organization, 2012). In addition to mood 2003; American Psychiatric Association, 2013). Their return to Received: May 31, 2017; Revised: August 11, 2017; Accepted: September 7, 2017 © The Author(s) 2017. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 128 provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Oluboka et al. | 129 previous functioning may have a slower trajectory compared in various brain areas, including the hippocampus ( Videbech with symptomatic improvement during treatment (Miller et al., and Ravnkilde, 2004; McKinnon et al., 2009; MacQueen and Frodl, 1998; Bech, 2005; Papakostas, 2009; IsHak et  al., 2011). Ongoing 2011). Hippocampal volume loss is more severe in patients with functional impairment may interfere with integration back into a longer duration of untreated depression (Sheline et al., 2003 ; daily life and in turn delay full functional recovery. Conversely, McKinnon et al., 2009; MacQueen and Frodl, 2011). More recently, a higher level of functioning at baseline may be associated with research has focused on whether antidepressant treatment can better outcomes after treatment (McIntyre et al., 2017). alter the course of brain deficits associated with MDD ( Duric and The Canadian Network for Mood and Anxiety Treatments Duman, 2013; Rotheneichner et al., 2014). To underscore the need (CANMAT) recommends pharmacotherapy as a first-line for optimizing treatment for patients with depression as rapidly treatment for moderate to severe MDD (Kennedy et  al., 2016 ). as possible, we review here English language publications over Numerous antidepressants are available for the treatment of the past 5 years examining effects of depression and antidepres- MDD, including selective serotonin reuptake inhibitors (SSRIs), sant treatment on hippocampal volume. While other brain areas serotonin–norepinephrine reuptake inhibitors, and other anti - have also been examined, we focused this discussion on the depressants (agomelatine, bupropion, mianserin, mirtazapine, hippocampus as an example, because it has been examined in and vortioxetine), all of which have Level 1 evidence and are numerous studies in treated and untreated depressed patients therefore recommended as first-line treatments ( Kennedy et al., in both cross-sectional and longitudinal studies. Excluding 2016). Despite the range of pharmacotherapy options, treatment bipolar and psychotic depression, our search yielded a total of of MDD to full symptomatic and functional recovery remains 235 articles. A  total of 33 primary articles reported research in challenging. Rates of remission are low for any given drug human depression, 19 of which were found to be relevant and (approximately ≤50%) across groups of patients evaluated in are summarized below (Table 1). antidepressant clinical trials (Thase et al., 2005 ; Machado et al., Recently published research identified in this search con - 2006) and may be lower among patients treated in clinical prac- firmed earlier findings that depression is associated with altera - tice (Trivedi et al., 2006; Moller, 2008). The achievement of both tions in brain morphometry and circuit dysfunction that can be symptom remission and full functional recovery after a trial observed as volume loss in the hippocampus and other areas of an antidepressant treatment is even more difficult ( Soares implicated in depression (Geerlings et  al., 2012; Sheline et  al., et al., 2014b), and functional recovery can lag behind symptom 2012; Arnone et al., 2013; Huang et al., 2013; Nugent et al., 2013 ; remission (Sheehan et al., 2011 ). Therefore, successful manage- Zhao et  al., 2014; Schmaal et  al., 2016). A  significant reduction ment of MDD necessitates development of a personalized treat - in hippocampal volume has been reported as early as the first ment plan that allows the individual patients to achieve full depressive episode (Zhao et  al., 2014), although other studies functional recovery in the most effective and efficient manner have found no volumetric differences between first episode (McIntyre et al., 2015; National Institute of Mental Health, 2015 ). patients and healthy controls (McKinnon et  al., 2009; Schmaal The aim of this article is to present recommendations for using et al., 2016). More severe symptoms of depression are associated a patient-centered approach to rapidly provide optimal pharma - with greater hippocampal volume loss (Huang et al., 2013; Taylor cological treatment to patients with MDD. First, we establish the et al., 2014; Elbejjani et al., 2015 ). importance of providing early, optimized treatment of MDD Treatment of depression is generally associated with an based on recent research exploring the effects of depression on increase in hippocampal volume (Schermuly et al., 2011; Huang brain structure and function, using the hippocampus as a well- et al., 2013; Tendolkar et al., 2013) or at least a slowing of volume studied example. Then, we present a consensus of expert opin - loss (Elbejjani et al., 2015), although this has not been observed ion on best practices for physicians to address both depressive in all studies (Schmaal et  al., 2016). Structural changes may symptoms and functional impairment in MDD, with a focus on differ in patients with MDD depending on clinical response to treating with a sense of urgency in the clinical practice setting. treatment. Increased hippocampus volume has also been cor- related with improvement in depressive symptoms: In several cross-sectional studies, hippocampal volume was significantly The Need for Early Optimized Treatment greater in patients who achieved remission from depression Clinicians have historically used a “start low and go slow” compared with nonremitters (Arnone et al., 2013; Nugent et al., 2013). Volume did not differ significantly between remitted MDD approach to pharmacotherapy for MDD, prescribing an initial antidepressant trial for up to 6 to 8 weeks before concluding that patients and healthy individuals (Arnone et  al., 2013; Nugent et  al., 2013; Taylor et  al., 2014). In unmedicated patients with the treatment has failed and an adjustment is warranted (Work Group on Major Depressive Disorder, 2010 ; Qaseem et al., 2008 ). depression, an inverse relation between duration of untreated depression and hippocampal volume has been reported (Arnone However, evidence suggests that MDD should be treated with a greater sense of urgency (Habert et  al., 2016). When depres- et al., 2013). Results of longitudinal studies are mixed; an asso- ciation between improvement in depression and increased sion is not treated with urgency, patient suffering is prolonged. Furthermore, delaying effective treatment may reduce the like- hippocampus volume has been observed in some but not all studies (Schermuly et al., 2011; Arnone et al., 2013; Phillips et al., lihood of both asymptomatic remission and functional recovery, and increase the time to achieve remission (Gormley et al., 1999; 2015). One study found that volumetric changes were associated with cognitive performance at baseline but not with depres- Okuda et  al., 2010; Bukh et  al., 2013; Ghio et  al., 2014). Failure to rapidly and effectively treat major depression may have last- sion severity or improvement (Schermuly et  al., 2011). Volume differences between remitters and nonremitters in some stud- ing effects on patients’ brain structure and function, which may worsen progressively with successive depressive episodes ies appeared to be due at least in part to hippocampal volume loss over time in nonremitters rather than volume recovery in (Moylan et al., 2013). Results of recent brain imagining research provide clear remitted patients (Furtado et al., 2013; Taylor et al., 2014; Phillips et al., 2015). In fact, a smaller hippocampal volume was associ- rationale for treating MDD as rapidly as possible. Untreated MDD is associated with damage to the brain, evident as loss of volume ated with lack of improvement in depression rating scale scores Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 130 | International Journal of Neuropsychopharmacology, 2018 Table 1. Recent Literature on Antidepressant Effects on Hippocampal Volume Deficits Reference Method Comparison Findings Cross-sectional analyses Geerlings et al., MRI ≥65 y; depressed, HC • Smaller volume in depressed (defined by CES-D 2012 score or AD use) vs HC • Smaller volume in AD users vs no AD use (defined as HC) Huang et al., 2013 MRI Treated depressed (AD), • Lower hippocampus, CA1-3, and DG volume in untreated depressed (no depressed vs HC and no AD vs AD AD; 10-pt lower HAM- • AD intermediate betw een no AD and HC for CA1-3 D ), HC Nugent et al., MRI Depressed, remitted, HC • Smaller volume hippocampus and thalamus in 2013 depressed vs remitted and vs HC • Remitted and HC did not differ Arnone et al., MRI Depressed, remitted, HC • V olume reduced in depressed vs remitted and HC; 2013* no difference between remitted and HC Zhao et al., 2014 MRI, meta-analysis Untreated depressed, HC • Smaller volume for depressed vs HC • Smaller volume in subgroup with first episode depression vs HC • No association with number of episodes Travis et al., 2015 MRI Depressed (most taking • Similar volume between groups, but differences in DG AD), HC • Duration of depression was negatively correlated with volume • No association between volume and memory scores Schmaal et al., MRI, meta-analysis Depressed (some taking • Smaller volume for depressed vs HC 2016 AD), HC • No volume difference in patients with first episode depression vs HC; smaller volume in patients with recurrent episodes • No significant effect of AD Longitudinal analyses Schermuly et al., MRI, Depressed, HC • No difference between depressed and HC 2011 4+ mo AD treatment • V olume increased in depressed during treatment; change in volume was associated with baseline function but not depression scores Sheline et al., MRI ≥60 y; depressed, HC • Smaller volume for depressed vs HC at baseline 2012 12 wk sertraline Remitters, nonremitters • Smaller volume predicted poorer MADRS score • Smaller volume in nonremitters vs remitters Husarova et al., MRS Depressed; baseline vs • Myoinositol/creatine and phosphocreatine ratio 2012 7–11 wk escitalopram or postbaseline negatively correlated with MADRS score at baseline venlafaxine (MADRS • Lac/creatine and phosphocreatine ratio, an indicator responders only) of damage or dysfunction, decreased after AD treatment Arnone et al., MRI Depressed, HC • V olume increase after treatment 2013* 8 wk citalopram • No difference between medicated and unmedicated remitters • Significant negative correlation between duration of untreated depression and hippocampal volume Furtado et al., MRI Responders vs • Reduction in volume in nonresponders vs responders 2013 3 mo TMS (some taking AD) nonresponders • No correlation with HAM-D score Tendolkar et al., MRI Depressed; baseline vs • Increased volume after ECT 2013 ECT treatment (TRD; previous posttreatment AD treatment) Godlewska et al., MRI Responders vs • No significant effects 2014 8 wk escitalopram nonresponders • T rend toward normalization of volume in responders Taylor et al., 2014 MRI ≥60 y; depressed, HC • No difference from baseline for HC or remitted 2-y AD treatment (mostly • Volume decrease over time for nonremitters sertraline) • Significantly less volume for nonremitters vs HC at follow up • Worsening or nonimproving MADRS associated with decreasing volume Elbejjani et al., MRI ≥65 y; history of depression • Baseline: smaller volume with greater symptoms in 2015 4 yr AD treatment vs no history women (nonrandomized) • Faster volume loss in women with history of depression vs no history • Slower loss with AD vs no AD in men with history of depression Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Oluboka et al. | 131 Table 1. Continued Reference Method Comparison Findings Phillips et al., MRI TRD; depressed, HC • No difference between depressed and HC at baseline 2015 6–12 mo AD treatment Remitters, nonremitters • Remitters increased in volume, nonremitters decreased Postmortem studies Boldrini et al., IHC; neural progenitor cells Untreated depressed, • More neural progenitor cells and capillary area 2012 capillaries treated depressed (SSRI in individuals treated with SSRIs vs untreated or TCA), NDC depressed and vs NDC • Capillary area, number of progenitor cells, and volume were correlated in treated depressed subjects Boldrini et al., IHC; granule neurons Untreated depressed, • More granule cells in some areas of the DG in 2013 treated depressed (SSRI individuals treated with SSRIs or TCAs; numbers or TCA), NDC were between untreated depressed and NDC • No difference in glia cell numbers Duric et al., 2013 Gene expression; cytoskeletal Depressed, NDC • Dysregulation of pre- and postsynaptic genes in proteins depressed subjects vs NDC Abbreviations: AD, antidepressant; CES-D, Center for Epidemiologic Studies-Depression; DG, denate gyrus; ECT, electroconvulsive therapy; HAM-D , 17-item Hamilton Rating Scale for Depression; HC, healthy control; IHC, immunohistochemistry; MADRS, Montgomery-Åsberg Depression Rating Scale; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NDC, nondepressed control; TCA, tricyclic antidepressant; TMS, transcranial magnetic stimulation; TRD, treatment-resistant depression; SSRI, selective serotonin reuptake inhibitor. *Included both cross-sectional and longitudinal analyses. (Taylor et  al., 2014) and was a significant predictor of poorer depression outcomes (Sheline et al., 2012 ) in patients with late- life depression. The continued presence of depressive symptoms may promote chronic neuronal loss and suppress neurogenesis in the hippocampus (Boldrini et al., 2012, 2013; Duric et al., 2013; Furtado et  al., 2013; Phillips et  al., 2015), and preclinical work (Duman and Aghajanian, 2012; Licznerski and Duman, 2013; Bortolotto et al., 2014) supports the hypothesis that depression may disrupt neural connections in mood-related circuits and provides preliminary evidence that treatment may ameliorate these processes. Evidence from these recent publications suggests that treat- ment may halt and even reverse progressive damage to brain areas associated with depression, underscoring the urgency of rapidly and fully treating depression. Additionally, the duration of untreated illness is a significant predictor of response, remis - sion, and time to remission (Gormley et al., 1999; Okuda et al., 2010; Bukh et al., 2013; Altamura et al., 2015). Related measures such as age at the onset of depression, time since the onset of Figure 1. Early optimized treatment is critical to bringing patients to full symp - tomatic and functional recovery. From ( Habert et al., 2016). depression, duration of the current episode, and the number of previous episodes may also predict treatment outcome (Warden their usual level of functioning, and feeling in emotional con- et  al., 2007; Howland et  al., 2008; Fava et  al., 2009; Seemuller trol….” (Zimmerman et al., 2006). Ultimately, while the remission et  al., 2010; Joel et  al., 2014). Reducing the time between the of symptoms is an important outcome, for patients, recovering onset of depression and optimization of treatment results in from depression implies more than the absence of depressive better short-term clinical outcomes, increases the likelihood of symptoms (Zimmerman et al., 2006). What steps can clinicians achieving full functional recovery (Habert et al., 2016), and, not- take to ensure each patient receives the best possible individu - ably, may reduce the burden of damage to brain areas (Arnone alized care, with no unnecessary delay? The following section et al., 2013; Nugent et al., 2013 ). presents guidance, based of published evidence and the com - To effectively restore a patient to full function, clinicians bined experience of the authors, on providing optimal pharma- must strive to deliver early optimized treatment (Figure  1) cological treatment to patients with MDD, as rapidly as possible. (Habert et  al., 2016). Optimal treatment of depression should address all symptoms and functional impairment, minim- ize antidepressant side effects, address barriers to adherence, How Does the Clinician Provide Early provide strategies for relapse prevention, and elevate patients’ Optimized Treatment for the Individual overall sense of well-being and quality of life (Gelenberg et al.; Patient with MDD? Zimmerman et al., 2012; Kennedy et al., 2016 ; Lam et al., 2016). A patient’s recovery must always be addressed in terms of their Screening and Diagnosis own definition of “well.” Zimmerman and colleagues noted the Identifying MDD patients as early as possible after illness onset primary goal of depression treatment for patients is “presence of positive mental health…feeling their usual self, returning to is an essential first step in optimizing treatment. However, Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 132 | International Journal of Neuropsychopharmacology, 2018 numerous agencies do not recommend routine screening for in those high-risk patients and address symptoms when they depression in adults unless adequate resources and services are are observed (Joffres et  al., 2013; Lam et  al., 2016). For adoles- available for subsequent diagnostic assessment and manage - cents (12–18  years), the US Preventive Services Task Force rec - ment (National Institute for Health and Clinical Excellence, 2009 ; ommends screening when resources are available to ensure an Joffres et  al., 2013; Lam et  al., 2016; Siu et  al., 2016). Concerns accurate MDD diagnosis with appropriate care and follow-up. with screening all adult patients include the lack of robust There is little evidence to support screening patients younger evidence supporting routine screening (due to the paucity of than 12 years of age (US Preventive Services Task Force, 2009). available data on its benefits and harms), the high likelihood An initial screen for depression can be as simple as asking the that patients who screen positive will have been previously 2 questions recommended in the National Institute for Health identified as suffering from depression, and the risk of iden - and Clinical Excellence (NICE) guidelines: “During the last month, tifying very mild depression that does not require treatment have you often been bothered by feeling down, depressed, or (Joffres et al., 2013; Keshavarz et al., 2013; O’Connor et al., 2016). hopeless? During the last month, have you often been bothered However, the assertion that mild depression does not require by having little interest or pleasure in doing things?” A  more treatment may not consider the possibility that an individual in-depth assessment using a validated instrument should fol- may have mild depressive symptoms related to a resolving (but low, if there is an affirmative response to either question. Given not yet resolved) depressive episode or may be experiencing the that no biological markers have been established for depression onset of an impending, more severe depressive episode. Other (Huang and Lin, 2015), objective screening questionnaires are subgroups of people in this mildly depressed population may critical tools to employ when assessing a depressed patient. Just include those individuals with chronically lower hedonic tone, as diabetes or hypertension would not be diagnosed without who could be more susceptible to develop either a major depres- blood glucose levels or blood pressure assessments, a diagnosis sive episode or what is described in the DSM-5 as dysthymia (or of MDD requires the measurement of symptoms and associated persistent depressive disorder) (Sternat et al., 2014; Sternat and functional impairment (American Psychiatric Association, 2013). Katzman, 2016). A number of validated assessment tools that incorporate MDD Still, the literature at present suggests that routine screen- diagnostic criteria are available, including both symptom scales ing is not recommended; rather, clinicians should consider and functional assessments ( Table  2). The authors recommend screening patients with risk factors for depression, as outlined the use of the 9-item Patient Heath Questionnaire (PHQ-9), a in Box 1 (National Institure for Health and Clinical Excellence, brief, self-administered assessment incorporating DSM diag- 2009; Lam et al., 2016), or be alert to the possibility of depression nostic criteria that patients can complete quickly and that may Box 1. Depression Screening in Primary and Secondary Care Settings CANMAT guidelines recommend screening patients with risk factors for depression (Lam et al., 2016): Clinical Risk Factors Symptom Risk Factors History of depression Unexplained physical symptoms Family history of depression Chronic pain Psychosocial adversity Fatigue High users of the medical system Insomnia Chronic medical conditions (especially cardiovascular Anxiety disease, diabetes, and neurological disorders) Substance abuse Other psychiatric conditions Times of hormonal challenge (e.g., peripartum) Screening A 2-question screen can be used for identifying patients that may require more detailed assessment (National Institute for Health and Clinical Excellence, 2009 ) 1. In the last month, have you been bothered by little interest or pleasure in doing things? 2. In the last month, have you been feeling down, depressed or hopeless? Patients who respond “yes” to either of these questions should be assessed with an instrument such as the PHQ (National Institute for Health and Clinical Excellence, 2009 ; Patient Health Questionnaire, 1999; Lam et al., 2016) Over the past 2 weeks, how often have you been bothered by any of the following problems, scored 0 (not at all) to 3 (nearly every day)? 1. Little interest or pleasure in doing things 2. Feeling down, depressed, or hopeless 3. Trouble falling asleep, staying asleep, or sleeping too much 4. Feeling tired or having little energy 5. Poor appetite or overeating 6. Feeling bad about yourself or that you’re a failure or have let yourself or your family down 7. Trouble concentrating on things, such as reading the newspaper or watching television 8. Moving or speaking so slowly that other people could have noticed. Or, the opposite - being so fidgety or restless that you have been moving around a lot more than usual 9. Thoughts that you would be better off dead or of hurting yourself in some way Abbreviation: CANMAT, Canadian Network for Mood and Anxiety Treatments. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Oluboka et al. | 133 Table 2. Screening/Monitoring Tools for the Clinic (Endicott and Dorries, 2009; Lam et al., 2016) Instrument Structure Reference Symptoms Patient Health Questionnaire 9 items, each scored 0–3 Kroenke and Spitzer, 2002 Quick Inventory for Depressive Symptomatology, 16 items, each scored 0–3 Rush et al., 2003 Self-Rated Clinically Useful Depression Outcome Scale 18 items, each scored 0–4 Zimmerman et al., 2008 Behavior and Symptom Identification Scale 32 items, each scored 0–4 Eisen et al., 1994 ) (BASIS-32) Function/quality of life Sheehan Disability Scale 3 items, each scored 0–10 Sheehan et al., 1996 World Health Organization Disability 36 items in 6 domains, each scored 1–5 Posl et al., 2007 Assessment Schedule II Lam Employment Absence and Productivity Scale 10 items, 3 open response and 7 scored on a 5-point, Lam et al., 2009) Likert scale Social Adjustment Scale, Self-Report Version 48 items in 6 domains, each rated on a 5-point, Likert Weissman and Bothwell, 1976 scale Social and Occupational Functioning Assessment Single scale, scored 0–100 Rybarczyk, 2011 Scale EuroQoL-5D Single scale, scored 0–100 EuroQoL, 1990 be administered repeatedly to monitor symptom response to obsessive-compulsive disorder, posttraumatic stress disorder, treatment (Kroenke and Spitzer, 2002). For a definitive diagnosis, or bipolar disorder, when a patient presents with depression the use of any assessment tools should always be coupled with commonly results in treatment-resistance because the comor- a clinician’s good judgement, a psychiatric interview, and add- bid condition is inappropriately or inadequately treated. When itional assessments to rule out other disorders ( Lam et al., 2016). clinicians understand which conditions may be associated Assessment tools also provide the clinician with a measure with a higher risk of MDD (e.g., substance abuse, low hedonic of the severity of specific depression symptoms or the degree tone, or attention deficit hyperactivity disorder [ADHD]; Kessler of functional impairment. Determining both the episode speci- et  al., 2003; Sternat et  al., 2014), they are better able to remain fiers and the severity of depression at diagnosis is critical to alert for signs of depression in patients with those conditions developing an appropriate treatment plan and establishing (Epstein et  al., 2014). An undiagnosed medical or psychiatric baseline measurements to monitor improvement during treat - comorbidity can interfere with response to MDD treatment ment (Kennedy et  al., 2016 ; Lam et  al., 2016). However, criteria (McIntyre et  al., 2015; Bron et  al., 2016). The 2015 Florida Best for depression severity provided by various guidelines are not Practice Psychotherapeutic Medication Guidelines for Adults consistent (Davidson, 2010). The DSM-5 and the International recommends differential screening for psychiatric and medical Classification of Diseases, Tenth Revision ( American Academy comorbidities (Florida Agency for Health Care Administration, of Professional Coders, 2013) (ICD-10) definitions for depression 2015), which is in line with the approach set forth by the severity differ based on the threshold numbers of symptoms National Institute of Mental Health. The National Institute of present during a depressive episode, intensity of symptoms, and Mental Health recommends the progression to more patient- the resulting impairments/disability (Davidson, 2010). Although centered diagnostic approaches that consider an individual’s the criteria are similar, a patient meeting the ICD-10 criteria for genetic, physiologic, and behavioral profiles to achieve a specific mild depression, for example, might have subthreshold depres- and informative diagnosis (National Institute of Mental Health, sion based on DSM-5 criteria (Davidson, 2010). The DSM-5 and 2015). Although subsets of patients with an increased risk for ICD-10 criteria for severity include both number of symptoms MDD have been noted (Box 1) ( National Institute for Health and and degree of impairment or disability (Davidson, 2010) The Clinical Excellence, 2009 ; Lam et  al., 2016), risk factors serve American Psychiatric Association, the British Association for only as a guide. Ultimately, the clinician must determine which Psychopharmacology, NICE, and CANMAT recommendations individual patients require additional screening for an MDD define MDD severity according to DSM criteria only ( Work diagnosis. Group on Major Depressive Disorder, 2010 ; Anderson et  al., 2008; National Instutute for Health and Clinical Excellence, Individualized Treatment Plan 2009; Bauer et  al., 2013; MacQueen et  al., 2016 ). CANMAT and The development of an individualized treatment plan includes American Psychiatric Association guidelines address psychia- identifying specific treatment goals and determining the best trists; NICE and British Association for Psychopharmacology strategies to employ to accomplish these goals ( Lam et al., 2016). guidelines address both specialists and primary care physicians. The ideal treatment plan takes into account the patient’s spe - Finally, because medical comorbidities can complicate cific array of symptoms and associated functional impairment, depression screening and diagnosis, clinicians should be aware together with the medical and lifestyle characteristics that of their role in both under- or misdiagnosis of MDD ( Huerta- might contribute to the success or failure of a given treatment, Ramirez et al., 2013; McGuire et al., 2014). Depression symptoms as outlined by the RDoC Initiative for developing new treat- may be missed in patients presenting with symptoms of comor- ments. The RDoC Initiative recommended treatment be based bid conditions, resulting in delayed diagnosis and treatment on individual patient characteristics, personal and medical (McGuire et al., 2014; Lam et al., 2016; Thase, 2016). Likewise, not history, and quality of life (National Institute of Mental Health, ruling out the presence of another psychiatric disorder, such as Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 134 | International Journal of Neuropsychopharmacology, 2018 2015). An individual patient’s treatment goals should encom- outcomes (Ashton et al., 2005; Cameron et al., 2014; Culpepper pass the concept of “treating-to-target”—treating the patient to et al., 2015). achieve the goal of full and sustained functional recovery across all aspects of MDD (McIntyre et  al., 2015). A  treating-to-target Antidepressant Treatment Selection approach includes asymptomatic remission, but also functional A key factor in achieving treat-to-target goals is the selection of recovery, including improvement in social, interpersonal, work, a treatment best matched to the individual patient. Rapid treat- and family domains. It is essential to consider that a patient’s ment optimization requires that antidepressant drug and dose concept of wellness may differ substantially from that of the selection is based on patients’ individual clinical characteristics treating physician (Zimmerman et  al., 2006; McIntyre et  al., rather than a habit-based, “one-size fits all” approach ( National 2015), and ultimately, it is the patient’s concept that is the most Institute of Mental Health, 2015 ; Habert et  al., 2016). To date, important treatment goal. pharmacogenetics/genomic biomarkers have yet to demon- A collaborative approach to developing and following the strate a positive impact on health outcomes in clinical practice; treatment plan is needed to achieve treating-to-target goals. however, future research may eventually prove biomarkers to be The physician and patient should decide together how best to beneficial in selecting appropriate antidepressants in specific address bothersome symptoms and return the patient to pre- patient populations (Dunlop and Mayberg, 2014; Leuchter et al., illness functioning. The treatment team may also include family 2014; Thase, 2014a). Some evidence indicates that antidepres - members, other clinicians (nurses, social workers, specialists), sant efficacy or tolerability may vary based on patient genotype. and those involved in other aspects of recovery, for instance For example, in clinical trials of venlafaxine (extended release addiction counselors (Work Group on Major Depressive Disorder, or immediate release), the cytochrome P450 (CYP) 2D6 poor 2010; Lam et al., 2016). This approach yields a more comprehen- metabolizer genotype is associated with significantly smaller sive MDD treatment plan and might also improve outcomes for mean improvements in depressive symptoms and significantly comorbid conditions (Teh et al., 2010 ; Jiang et al., 2011). lower rates of remission vs those with the extensive metabolizer Treatment plans often evolve over time, as patients pro- phenotype (Lobello et  al., 2010). In depressed patients admin- gress or encounter obstacles to recovery ( McIntyre et al., 2015). istered escitalopram, CYP2D6 genotypes yielding more rapid Given that about one-half of patients who initiate an anti - metabolism were significantly associated with a slower time depressant will fail to achieve remission (Thase et  al., 2005 ; to remission, and CYP2C19 poor metabolizers had significantly Machado et al., 2006; Thase et al., 2007 ), several treatment steps higher serum escitalopram levels compared with extensive may be needed to achieve successful outcomes. Treatment fail - metabolizers (Tsai et  al., 2010). Plasma vortioxetine levels are ures may result from the lack of treatment efficacy, noncompli - reported to be twice as high in CYP2D6 poor metabolizers com- ance, or poor tolerability. An effective treatment plan adjusts pared with CYP2D6 extensive metabolizers (Zhang et al., 2015). to address these obstacles to optimize treatment as rapidly as These findings suggest that certain patients may require thera - possible (Culpepper et al., 2015; Habert et al., 2016). For patients peutic drug monitoring and/or dose adjustment for efficacy or with MDD who do not respond to an initial treatment, phy- safety if antidepressant drugs whose exposure or efficacy vary sicians may consider increasing the dose, adding adjunctive with metabolizer genotype are prescribed (Probst-Schendzielorz treatment, or switching to an antidepressant with a differ - et al., 2015; Zhang et al., 2015). ent mechanism of action (Kennedy et al., 2016 ). However, evi- In the absence of reliable biomarkers, before selecting an dence suggests that outcomes are less robust for patients who antidepressant, all relevant clinical factors that may be asso- require subsequent treatment steps or when changes to an ciated with differences in drug efficacy should be considered. effective treatment are delayed. Remission rates for patients Such factors include age, illness severity, predominant symp- in 4 successive treatment steps in the Sequenced Treatment toms (e.g., agitation vs retardation), comorbidities, areas of Alternatives to Relieve Depression trial dropped progressively, functional impairment, and previous antidepressant treat - from 37% at step 1 to 13% at step 4 (Rush et al., 2006b). Patients ment history (Uher et  al., 2012; Kennedy et  al., 2016). While who remitted during the first treatment step experienced antidepressants may be similar in efficacy overall ( Work Group greater improvements in function compared with patients who on Major Depressive Disorder, 2010 ; Gartlehner et  al., 2011; remitted at step 2 (Trivedi et al., 2013). Providing a longer treat - Schueler et  al., 2011), published literature suggests there may ment trial (8 weeks vs 4 weeks) before switching is associated be potential benefits of some drugs in individuals with specific with poorer functional outcomes, even among patients who symptoms or comorbid conditions (Sternat and Katzman, 2016). remit on the second treatment (Romera et al., 2012). Research The CANMAT guidelines include recommendations for specific examining early response to antidepressant treatment sug- antidepressant drugs or classes based on clinical specifiers and gests that treatment adjustment can be considered after just dimensions of MDD, although the evidence is not of the highest 2 to 4 weeks of treatment (Habert et  al., 2016; Kennedy et  al., quality (Kennedy et  al., 2016). Analysis of antidepressant effi - 2016). Taken together, these findings suggest that developing cacy in patient subpopulations has not been published for all a plan that is focused on early optimization of treatment, with antidepressant drugs, and understanding effectiveness of treat- continued measurement-based follow-up to ensure the patient ment among individuals with specific demographic, medical, is progressing, is a critical step in bringing the patient to full or genetic characteristics remains an important research goal functional recovery. (National Institute of Mental Health, 2015 ). A successful treatment plan also includes patient education Characteristics that may affect treatment tolerability or regarding therapy options, possible associated adverse effects, adherence for individual patients are also important considera - and the expected course of recovery. A patient who knows what tions. These include past response, potential sensitivity to side to expect from an antidepressant treatment comprehends effects, family history, potential for drug-drug interactions, sim - when and why treatment adjustments might occur and under - plicity of use, issues associated with abrupt discontinuation, stands the value of long-term antidepressant treatment is more cost, and branded vs generic formulations ( Kennedy et al., 2016 ). likely to be adherent to the treatment plan and achieve positive Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Oluboka et al. | 135 Tolerability and compliance can be important differentiators In the majority of studies, improvement was defined as a per - when it is not clear that one antidepressant drug or class may centage change in depression scale scores from baseline (often hold an efficacy advantage for a particular patient ( Kennedy ≥20% change) assessed at 1 to 4 weeks after treatment initiation. et  al., 2016). Although adverse events are associated with all Importantly, lack of early improvement (negative predictive drugs, specific antidepressants are associated with higher rates value) appears to be a more accurate predictor of eventual treat - of particularly troublesome side effects, such as weight gain and ment outcome than is achieving early improvement (positive sexual dysfunction (Ashton et al., 2005; Serretti and Chiesa, 2009; predictive value) (Habert et  al., 2016). These data suggest that Serretti and Mandelli, 2010; Clayton et al., 2014). Tolerability con- in clinical practice, physicians can use a lack of improvement cerns are heightened for patients who have comorbid condi- early in treatment as an indicator that modification of therapy tions that could be worsened by antidepressant effects, or who is needed. take concomitant medications likely to contribute to drug-drug Most studies examining the predictive value of early interactions (Manolopoulos et  al., 2012; Kennedy et  al., 2016 ; improvement used a 2-week time point to assess early treat- Thase et al., 2016). Efficacy and tolerability differences between ment response (Habert et al., 2016). Although 2 weeks is not an drugs must be balanced based on the needs of the individual adequate trial for efficacy, information from the first week or patient (Gartlehner et al., 2005; Machado et al., 2006; Gartlehner two can be useful for making dose adjustments (Kennedy et al., et al., 2008a, 2008b; Cipriani et al., 2009). 2016). Given that increases of 2 to 3 times an initial dose are Physicians may also consider the importance of prescription common, delaying dose adjustments results in patients being insurance coverage when selecting an antidepressant treat- under-dosed and increases time to recovery (Mohr et al., 2015). ment for a specific patient. A recent report suggests that most Baseline and weekly assessments of both depressive symptoms US healthcare plans implement restriction strategies other than and functioning are therefore recommended (Szegedi et  al., complete exclusion (e.g., tier placement, administrative restric- 2009; Lam et al., 2011). tions) to manage the cost and utilization of newer antidepres- The CANMAT algorithm for managing inadequate anti- sant treatments (Hodgkin et al., 2015). Most older, less expensive depressant response states that a dose increase should be the agents are unrestricted. The selection of branded vs generic first step in optimizing treatment and recommends considering medications should be considered. Generic medications provide a switch or addition of adjunctive treatment after 2 to 4 weeks a lower cost option. However, even though approval of a generic if no improvement is noted with a dose adjustment, or a dose medication requires a demonstration of bioequivalence, which increase is not tolerated (Kennedy et  al., 2016 ). As with initial does sometimes fail ( Chenu et al., 2009 ; Woodcock et al., 2012), decisions regarding treatment choice, a range of clinical fac- there nonetheless may be efficacy or tolerability differences for tors should be considered in determining a second treatment some patients taking generic drugs, possibly related to differ- step (Table  3) (Kennedy et  al., 2016 ). Switching to a new anti- ence in excipients ( Gallelli et al., 2013 ; Andrade, 2015). Discussing depressant may be appropriate when the initial drug has poor insurance coverage may inform antidepressant selection, as tolerability or when a patient prefers a simpler regimen with a restrictions and higher copay requirements may preclude single medication. An adjunctive medication can complement patients from following through with their prescription. the initial antidepressant drug, targeting specific side effects A review of nonpharmacological interventions is beyond the and residual symptoms when there is a partial response, while scope of this article; however, it is important to note that psy- giving the first drug a longer trial ( Cameron et al., 2014; Kennedy chological therapies are recommended as first-line treatment or et al., 2016). as an adjunctive to pharmacological therapy for some patients Table  3. Factors to Consider in Choosing Between Switching to (Parikh et al., 2016). Complementary and alternative medicines Another Antidepressant Monotherapy or Adding an Adjunctive have proven beneficial for some patients with MDD, particularly Medication (Level 3 Evidence) those with mild to moderate depression, or as adjunctive treat- ment in patients with moderate to severe depression (Ravindran Consider switching to another antidepressant when: et al., 2016). As full functional recovery is all too commonly not It is the first antidepressant trial. achieved with pharmacological treatment alone, consideration There are poorly tolerated side effects to the initial of nonpharmacological interventions may prove essential to antidepressant. achieving optimized treatment (McIntyre et al., 2015). There is no response (<25% improvement) to the initial antidepressant. There is more time to wait for a response (less severe, less Assessment of Early Improvement for Early functional impairment). Optimized Treatment Patient prefers to switch to another antidepressant. Consider an adjunctive medication when: Once an initial antidepressant selection is made, physicians There have been 2 or more antidepressant trials. should be thorough and persistent in monitoring patient The initial antidepressant is well tolerated. response through clinical interviews and by using validated There is partial response (>25% improvement) to the initial measurement tools (Papakostas, 2016). Maintaining initial antidepressant. treatment for up to 8 weeks (Work Group on Major Depressive There are specific residual symptoms or side effects to the initial Disorder, 2010) before making adjustments is outdated. Instead, antidepressant that can be targeted. clinicians must shift to evidence-based and patient-specific There is less time to wait for a response (more severe, more prescribing with rapid optimization of treatment, closely moni - functional impairment). toring efficacy and tolerability over the first 1 to 4 weeks of Patient prefers to add on another medication. treatment to heighten adherence and reduce time spent on inef - fective medication ( Habert et al., 2016; Lam et al., 2016). With permission from (Kennedy et al., 2016 ). A growing body of research has demonstrated that early For the initial antidepressant trial. In subsequent trials, lack of response (<25% improvements in depressive symptoms and functioning predict improvement) may not be a factor for choosing between switch and adjunctive eventual remission or recovery (reviewed in Habert et al., 2016). strategies. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 136 | International Journal of Neuropsychopharmacology, 2018 Measurement-based care requires the use of validated tools gain, sexual dysfunction, failure of patients to perceive bene- for monitoring early improvement in symptoms and func - fits of treatment, and premature discontinuation of treatment tion (Lam et  al., 2016), and numerous tools are available for after symptoms have improved (Masand, 2003; Ashton et  al., the clinical setting ( Table  2). Symptom assessments used in 2005; Burra et al., 2007; Fortney et al., 2011). Clinical experience clinical trials (17-item Hamilton Rating Scale for Depression, has shown that patients are reluctant to start another anti - Montgomery–Åsberg Depression Rating Scale) are too time-con- depressant following a long trial of an ineffective antidepres- suming and burdensome for application in daily clinical prac- sant. Compliance with the second antidepressant may also be tice. Guideline-based validated instruments such as the PHQ-9 compromised if a patient mistakes withdrawal symptoms from or Quick Inventory of Depressive Symptomatology, in contrast, the previous medication for side effects of the new one. Using a are fast, easy, and self-administered (Kroenke and Spitzer, 2002; crossover technique to taper one antidepressant while initiating Rush et al., 2006a; Thase, 2014b). a new one may reduce or eliminate discontinuation symptoms Because treatment goals include a full functional recov- (Masand, 2005). SwitchRx.ca offers suggested crossover sched- ery and return to premorbid quality of life, improvements in ules for antidepressant switches (Canadian Network for Mood functional impairment should also be monitored (Lam et  al., and Anxiety Treatments, 2017). 2016). The Sheehan Disability Scale is a useful tool for identify - To prevent early discontinuation and optimize patient adher- ing functional impairment and severity of functional disability ence to treatment, physicians should choose antidepressants (Sheehan, 2000 ; Sheehan and Sheehan, 2008 ). Similarly, various with improved tolerability profiles, use the fewest medications patient-administered scales are available for evaluating quality possible, and adjust dosages/treatment to minimize adverse of life (Endicott and Dorries, 2009; Lam et al., 2016). Improvement effects (Cameron et al., 2014; Culpepper et al., 2015). Data from in function and quality of life often lags behind symptom remis- the Medical Expenditure Panel Survey for 1996 to 2001 showed sion in patients with MDD (Bech, 2005; Sheehan and Sheehan, that >40% of patients treated for a first depressive episode dis - 2008; IsHak et al., 2011). Similar to symptom improvement, func- continued antidepressant treatment within the first 30  days tional improvement in the first 2 weeks of treatment is predict - (Olfson et al., 2006). Poor tolerability was identified as a primary ive of functional outcomes (Soares et al., 2014b), indicating that reason for noncompliance (Demyttenaere et al., 2001). In a sur- weekly assessment of function and quality of life can be valu - vey of 350 adults with MDD, adverse events were the second- able for considering adjustments to the treatment plan. Other most common cause of discontinuing an antidepressant (after specialized outcome scales may be needed to screen for comor- lack of efficacy) and second-most common reason for noncom - bid conditions, both at initial assessment and when adjusting pliance (after forgetting to take medication) (Ashton et al., 2005). the treatment plan in the case of treatment failure. Because Weight gain, sexual dysfunction, and fatigue/lack of energy were patients with MDD have a 2-fold higher prevalence of ADHD the most troublesome side effects and among the most likely to relative to the general population and the presence and sever- result in noncompliance or treatment discontinuation (Ashton ity of comorbid ADHD can inform treatment selection for both et  al., 2005). Physicians should closely monitor antidepressant conditions (Canadian Attention Deficit Hyperactivity Disorder tolerability, including the most common and most trouble- Resource Alliance, 2011; Bond et  al., 2012), the authors recom- some side effects for the prescribed drug or class, utilizing dose mend assessing for ADHD using the Adult ADHD Self-Report adjustment, pharmacological or nonpharmacological treatment Scale (Kessler et  al., 2005) in patients with treatment-resistant of the adverse effect, or switching to a different drug to mitigate depression. the impact on compliance ( Anderson et al., 2008; Work Group on In addition to in-office assessments, internet-based tools Major Depressive Disorder, 2010 ). allow patients to monitor depressive symptoms and functional Additional steps to optimize patient adherence may involve impairment between office visits. One such tool is MoodFx, an patient education, setting realistic patient expectations, employ - interactive website focusing on depression and anxiety (Work ing collaborative care systems, and providing adequate follow- With Us Program, 2014; Mohr et  al., 2015; MoodFX website, up care (Cameron et  al., 2014; Culpepper et  al., 2015). Patients 2016). Web-based tools allow patients to monitor their symp- who are closely monitored by their healthcare providers have toms, cognitive deficits, and workplace functioning using vali - higher rates of treatment adherence. Physicians can maintain dated questionnaires (PHQ-9, the Generalized Anxiety Disorder patient communication via regular office visits or augment Questionnaire-7, the Lam Employment Absence and Productivity scheduled appointments using internet-based tools such as Scale, the Perceived Deficits Questionnaire-5, and items on gen - MoodFx (Work With Us Program, 2014) or MedLink ( Mohr et al., eral functioning and quality of life from the Clinically Useful 2015). Tools for assisting the physician in monitoring adher - Depression Outcome Scale). Patients can monitor improvement ence include electronic monitoring, pill counts, blister-packing and share results with their clinician, which supports their medications, medication diaries, patient self-reporting, chart ongoing engagement in the treatment process. reviews, easy availability of prescription renewal, and phar - macy records (Osterberg and Blaschke, 2005; Velligan et al., 2006 ; Byerly et al., 2007; Nakonezny et al., 2008 ; van Onzenoort et al., Treatment Adherence 2012; Faurholt-Jepsen et al., 2014; Sutton et al., 2014; Orrell et al., Medication adherence is critical to achieving full, functional 2015). recovery and is one of the major challenges hindering opti- mal treatment of MDD (Kohler et al., 2012; Ho et al., 2015; Lam Long-Term Treatment Plan et  al., 2016). Lack of adherence to antidepressant treatment is associated with poor treatment outcomes, including a greater Patients benefit from understanding the chronic nature of MDD risk of relapse (Gopinath et  al., 2007), increased impairments and the need for a long-term plan to ensure they return to pre- in functioning (Burton et  al., 2007), and greater risk of suicide illness functioning and lessen the risk of relapse or recurrence. (Ruengorn et  al., 2012). Obstacles to adherence include poor Clinical evidence supports maintenance treatment of MDD with tolerability, social stigma, inadequate patient education, low pharmacotherapy, psychotherapy, and other non-pharmaco - motivation, medication cost, delayed onset of efficacy, weight therapies (Moller, 2008; Glue et  al., 2010 ; Lam et  al., 2016). The Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Oluboka et al. | 137 expected duration of antidepressant treatment should be dis- Clarke et al., 2015; Lam et al., 2016). CANMAT recommends cog- cussed, and patients should be made aware of medication side nitive behavioral therapy as a first-line maintenance treatment effects that may occur later in treatment as well as possible dis- for depression (Parikh et al., 2016). The long-term treatment plan continuation symptoms. Long-term maintenance pharmaco- must be individualized to each patient and evolve as the patient therapy should be considered for patients who have risk factors progresses through treatment ( McIntyre et al., 2015). for recurrence of depression ( Work Group on Major Depressive Disorder, 2010; Lam et al., 2016). Nonpharmacological interven- Conclusions tions for MDD, including psychotherapy, behavior modification, and implementation of positive lifestyle habits (i.e., physical Recent studies suggest that delaying the treatment of MDD fitness, nutrition, weight loss, stress reduction/tolerability exer - can result in progressive damage to brain areas associated cises, establishing a strong social network), may have long-term with depression and that pharmacotherapy may halt and even benefits, including mitigation of recurrence ( Houle et  al., 2013 ; reverse those effects, underscoring the importance of rapidly Box 2. Q and A When do you screen for depression, and what tools do you use? • Consider screening patients with risk factors for depression, or be alert to the possibility of depression in high-risk patients, following up when clinical symptoms are noted (Joffres et al., 2013; Lam et al., 2016) • A positive response on an initial 2-question screen (“During the last month, have you often been bothered by feeling down, depressed or hopeless? During the last month, have you often been bothered by having little interest or pleasure in doing things?”) can be followed up using the PHQ-9 ( Kroenke and Spitzer, 2002) How do you determine treatment goals for an individual patient? • An individual patient’s treatment goals focus on full and sustained functional recovery across all aspects of MDD (McIntyre et al., 2015). The goal should include symptomatic remission, but also functional recovery, including societal, interpersonal, work, and family domains, and any other health outcomes defined by the individual patient and/or clinician ( Zimmerman et al., 2006; McIntyre et al., 2015). • The patient’ s concept of remission may differ from that of the treating physician (Zimmerman et al., 2006). What factors do you consider in selecting an antidepressant? • The indi vidual patient’s diagnostic specifiers, symptoms and severity, areas of impairment, other clinical characteristics, and medical history together with patient biases and preferences for treatment should be considered when choosing an antidepressant (National Institute of Mental Health, 2015 ; Habert et al., 2016; Kennedy et al., 2016 ). • A range of factors (age, gender, MDD severity, predominant symptoms, diagnostic subtype, and comorbidities) could be associated with differences in efficacy or tolerability for specific drugs or classes ( Uher et al., 2012; Kennedy et al., 2016 ). What baseline assessments (for symptoms and function) do you use? How do you assess progress during treatment? What scales do you use? • The PHQ-9 and SDS ar e brief, validated scales that can be used to measure baseline symptoms of depression and functional impairment, respectively (Kroenke and Spitzer, 2002). • The same instruments can be administer ed weekly during acute treatment to assess changes in symptoms and function during treatment. • Patients can also monitor changes in symptoms and share results and concerns with their clinician via mobile device applications (Mood Disorders Society of Canada 2014; Mohr et al., 2015). How early do you optimize the treatment step when needed? • Early improvements in depressive symptoms and in functioning, measured 1 to 4 weeks after initiation of treatment, predict later remission or recovery ( Koran et al., 1995; Szegedi et al., 2003 ; Henkel et al., 2009 ; Kok et al., 2009; Szegedi et al., 2009 ; Lin et al., 2011; Joel et al., 2014 ; Lam et al., 2014; Soares et al., 2014a) • Information from the first week or 2 of treatment can be useful for making dose adjustments ( Kennedy et al., 2016 ); a switch to another antidepressant or addition of adjunctive treatment should be considered after 2 to 4 weeks if no improvement is noted with a dose adjustment or if the patient does not tolerate the dose increase (Kennedy et al., 2016 ). What are the major obstacles to adherence? How do you monitor for adherence? • Obstacles to adherence include poor tolerability, social stigma, inadequate patient education, lack of patient motivation, concerns about medication cost, weight gain, sexual dysfunction, delayed onset of efficacy, failure of patients to perceive benefits of treatment, and premature discontinuation of treatment after symptoms have improved ( Masand, 2003; Ashton et al., 2005; Burra et al., 2007; Fortney et al., 2011) • T ools for monitoring adherence to antidepressant medication include electronic monitoring, pill counts, medication diaries, patient self-reporting, chart reviews, prescription renewal, and pharmacy records ( Osterberg and Blaschke, 2005; Velligan et al., 2006; Byerly et al., 2007; Nakonezny et al., 2008 ; Faurholt-Jepsen et al., 2014; Sutton et al., 2014; Orrell et al., 2015). How do comorbid conditions (psychiatric or general medical) affect a long-term treatment plan? • Because the presence of comorbid psychopathologies is a risk factor for recurrence of depression, long-term treatment is recommended for patients with comorbid conditions (Lam et al., 2016). • T reatment efficacy for both antidepressant and psychological treatments may vary with medical of psychiatric comorbidities, so these should be taken into account when developing a long-term treatment plan ( Kennedy et al., 2016 ; Parikh et al., 2016). • The long-term tr eatment plan should also include addressing comorbid conditions in the maintenance period (Lam et al., 2016). Abbreviations: MDD, major depressive disorder; PHQ-9, 9-item Patient Health Questionnaire; SDS, Sheehan Disability Scale. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/128/4107968 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 138 | International Journal of Neuropsychopharmacology, 2018 treating depression to full recovery. Our recommendations for Eli Lilly, Euthymics, Janssen, Lundbeck, Merck, Otsuka, Pfizer, delivering rapidly optimized care are summarized in Box 2.  Pierre Fabre, Servier, Shire, Takeda, and Valeant. Early optimized treatment of MDD, using measurement-based care, and customizing treatment to the individual patient may References afford the best possible outcomes for each patient and increase the likelihood they will achieve full functional recovery. Using a Altamura AC, Serati M, Buoli M (2015) Is duration of illness really patient-centered approach throughout MDD treatment entails influencing outcome in major psychoses? Nord J Psychiatry aligning the treatment plan with each patient’s individual char- 69:1–15. acteristics and preferences and expectations for treatment, American Academy of Professional Coders (2013) ICD-10 including, most critically, their own definition of wellness and resource: coding for major depressive disorder.http://cloud. goals for recovery. aapc.com/documents/Depressive-Disorder-ICD-10-BH.pdf. American Psychiatric Association (2013) Major depressive dis - order. In: Diagnostic and statistical manual of mental disor - Acknowledgments ders (DSM-5), 5th ed, pp160–168. Washington, DC: American This review was supported by Pfizer Canada Inc. Medical writing Psychiatric Association. Anderson IM, Ferrier IN, Baldwin RC, Cowen PJ, Howard L, Lewis support was provided by Kathleen Dorries at Peloton Advantage and was funded by Pfizer. 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Dr. Boldrini M, Santiago AN, Hen R, Dwork AJ, Rosoklija GB, Tamir H, Milev has served on advisory boards or similar committees for Arango V, John Mann J (2013) Hippocampal granule neuron AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Lundbeck, number and dentate gyrus volume in antidepressant-treated Otsuka, Pfizer, Servier, and Shire; has participated in clinical and untreated major depression. Neuropsychopharmacology trials or studies for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, 38:1068–1077. Lundbeck, Brain Cells, and Pfizer; has received honoraria or other Bond DJ, Hadjipavlou G, Lam RW, McIntyre RS, Beaulieu S, fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Lundbeck, Schaffer A, Weiss M (2012) The Canadian Network for Mood Otsuka, Pfizer, and Sunovion; and has received research grants and Anxiety Treatments (CANMAT) task force recommenda- from CIHR, OMHF, OPGRS, OBI, and CANBIND. 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International Journal of NeuropsychopharmacologyOxford University Press

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