Guideline sources The following summarized guidelines for the evaluation and management of major depressive disorder (MDD) are prepared by our editorial team based on guidelines from the European Society of Medical Oncology (ESMO 2023), the American Society of Clinical Oncology (ASCO 2023), the American College of Physicians (ACP 2023), the United States Department of Defense (DoD/VA 2022), the American Psychiatric Association (APA 2019; 2010), the U.S. Preventive Services Task Force (USPSTF 2019; 2016), the American Academy of Pediatrics (AAP 2018), and the Canadian Task Force on Preventive Health Care (CTFPHC 2013). 1 2 3 4 5 6 7 8 10 11 12 13 14 14 14 14 15 Definition https://web.pathway.md/diseases/recOMiCCPIv46TowQ 1/15 6/29/23, 6:18 AM Major depressive disorder Pathway MDD is a mood disorder characterized by a persistent feeling of sadness that represents a change from previous functioning, often accompanied by loss of interest and alterations in cognition, sleep, and appetite. 14 Epidemiology The pathogenesis of MDD is complex, and remains poorly understood. Heritability is estimated at 35%. Predisposing genetic vulnerabilities interact with adverse and protective environmental factors to produce disease. At least some of the environmental effects are mediated through epigenetic mechanisms. 14 Pathophysiology In the United States, the 12-month and lifetime prevalence of MDD are estimated at 10.4% and 20.6%, respectively. 15 Disease course Key clinical manifestations include alterations in behavior and mood, impaired cognitive function, and suicidal ideation. 14 Prognosis and risk of recurrence MDD increases the risk of mortality by 60-80%. The contribution of MDD to all-cause mortality is estimated at up to 10%. 14 Guidelines 1. Screening and diagnosis Indications for screening, adults: As per DoD/VA 2022 guidelines, obtain screening for depression in all patients not currently receiving treatment for depression. B As per USPSTF 2016 guidelines, obtain screening for depression in the general adult population, including pregnant and postpartum women. Implement screening with adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up. B As per CTFPHC 2013 guidelines, do not obtain routine screening for depression in adults at average risk of depression. D Indications for screening, children and adolescents: As per AAP 2018 guidelines: Obtain annual screening for depression (MDD or depressive disorders) with a formal self- report screening tool either on paper or electronically (universal screening) in adolescents aged 12 years. B https://web.pathway.md/diseases/recOMiCCPIv46TowQ 2/15 6/29/23, 6:18 AM Major depressive disorder Pathway Identify and systematically monitor over time for the development of a depressive disorder by using a formal depression instrument or tool (targeted screening) in patients with depression risk factors (such as a history of previous depressive episodes, a family history, other psychiatric disorders, substance use, trauma, psychosocial adversity, frequent somatic complaints, or previous high-scoring screens without a depression diagnosis). B As per USPSTF 2016 guidelines: Obtain screening for MDD in adolescents aged 12-18 years. Implement screening with adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up. B Insufficient evidence to assess the balance of benefits and harms of screening for MDD in children aged 11 years. I 2. Classification and risk stratification Assessment of severity: consider using a quantitative measure of depression severity in the initial treatment planning and monitoring treatment progress at regular intervals to guide shared treatment decision-making in patients with MDD. C 3. Diagnostic investigations Initial evaluation: obtain a thorough diagnostic assessment to establish the diagnosis of MDD, identify other psychiatric or general medical conditions requiring attention, and develop a comprehensive plan for treatment. A Show 5 more Functional evaluation: Assess the patient's activity in life including work, school, family, social relationships, leisure activities, or maintenance of health and hygiene, and determine the presence, type, severity, and chronicity of any dysfunction. A Aim at maximizing the patient's level of functioning as well as helping the patient to set specific goals appropriate to existing functional impairments and symptom severity when developing a treatment plan. A Psychosocial evaluation: assess for issues relating to the family situation and family history, including mood disorders and suicide, as an important element of the initial evaluation because they can also affect treatment planning. A Show 4 more Patient safety evaluation: Obtain a careful and ongoing evaluation of suicide risk in all patients with MDD, including: specific inquiry about suicidal thoughts, intent, plans, means, and behaviors identification of specific psychiatric symptoms (such as psychosis, severe anxiety, substance use) or general medical conditions likely to increase the likelihood of acting on suicidal ideas https://web.pathway.md/diseases/recOMiCCPIv46TowQ 3/15 6/29/23, 6:18 AM Major depressive disorder Pathway assessment of past and, particularly, recent suicidal behavior delineation of current stressors and potential protective factors (such as positive reasons for living, strong social support) identification of any family history of suicide or mental illness. A Show 4 more Pharmacogenetic testing: insufficient evidence to recommend for or against pharmacogenetic testing to help guide the selection of antidepressants in patients with MDD. I Landmark trials: PRIME Care In adults with major depressive disorder who were initiating or switching treatment with a single antidepressant, pharmacogenomic-guided testing was superior to usual care with respect to estimated chance of no drug-gene interaction. David W Oslin et al. JAMA. 2022 Jul 12. Screening for HIV: consider assessing the risk and screening for human immunodeficiency virus given the significant number of patients with unrecognized human immunodeficiency virus infection and the availability of effective treatment. B 4. Medical management General principles: collaborate with the patient in decision-making and attend to the patient's preferences and concerns about treatment. A Show 9 more Setting of care: As per VA 2022 guidelines, use collaborative/integrated care models in patients with MDD being treated in the primary care setting. A Show 2 more As per APA 2010 guidelines, determine the least restrictive setting for treatment to address the patient's safety and promote improvement in the patient's condition. A Show 5 more Initial therapy: As per ACP 2023 guidelines, consider offering monotherapy with CBT as initial treatment in patients in the acute phase of mild MDD. C Show 2 more As per VA 2022 guidelines, offer either psychotherapy or pharmacotherapy as monotherapy based on patient preferences in patients with MDD. Offer other treatment strategies, such as augmentation, combination treatment, switching treatments, or non-first-line treatments based on factors including treatment response, severity, and chronicity. A https://web.pathway.md/diseases/recOMiCCPIv46TowQ 4/15 6/29/23, 6:18 AM Major depressive disorder Pathway Show 8 more Updated evidence: LIGHTMind In adults experiencing mild-to-moderate depression, mindfulness-based cognitive therapy self-help was superior to CBT self-help with respect to patient health questionnaire score at 16 weeks post-randomization. Clara Strauss et al. JAMA Psychiatry. 2023 Mar 22. As per APA 2019 guidelines, offer either monotherapy (psychotherapy or antidepressant therapy) or combined therapy as initial treatment in the context of sharing decision-making with the patient when considering options. A Show 4 more Maintenance therapy: As per VA 2022 guidelines: Continue antidepressants at the therapeutic dose for 6 months to decrease the risk of relapse in patients with MDD after achieving remission with antidepressants. A Consider offering a course of CBT, interpersonal therapy, or mindfulness-based cognitive therapy during the continuation phase of treatment (after achieving remission) in patients with MDD at high risk for relapse or recurrence (such as 2 prior episodes, unstable remission status). C As per APA 2019 guidelines, consider offering psychotherapy (CBT, mindfulness-based cognitive therapy, or interpersonal psychotherapy) rather than antidepressant therapy or usual treatment to prevent relapse in adult patients with MDD in remission. C Management of inadequate response: As per ACP 2023 guidelines, consider offering any of the following options in patients in the acute phase of moderate-to-severe MDD not responding to initial treatment with an adequate dose of a second-generation antidepressant: switch to or augment with CBT switch to a different second-generation antidepressant or augment with a second pharmacologic treatment. C As per VA 2022 guidelines, consider offering a combination of pharmacotherapy and evidence- based psychotherapy for the treatment of patients with persistent (duration > 2 years) or recurrent ( 2 episodes) MDD. C Show 4 more As per APA 2019 guidelines, offer any of the following options in adult patients with depression not responding or only partially responding to initial antidepressant therapy: switching to cognitive therapy switching to another antidepressant medication. A Show 2 more https://web.pathway.md/diseases/recOMiCCPIv46TowQ 5/15 6/29/23, 6:18 AM Major depressive disorder Pathway Therapies with no evidence for benefit: As per VA 2022 guidelines, do not offer the following or other unapproved treatments in patients with MDD outside a research setting: psilocybin MDMA cannabis deep-brain stimulation. D Show 2 more As per APA 2019 guidelines, insufficient evidence to recommend any of the following in patients with MDD: tai Chi acupuncture monotherapy omega-3 fatty acid monotherapy SAM monotherapy combination of second-generation antidepressants and acupuncture combination of second-generation antidepressants and omega-3 fatty acid combination of second-generation antidepressants and exercise. I Updated evidence: VITAL-DEP In adults aged 50 years at risk of incident depression or at risk of recurrent depression, omega-3 was inferior to placebo with respect to the incidence of of depression or clinically relevant depressive symptoms. Olivia I Okereke et al. JAMA. 2021 Dec 21. 5. Nonpharmacologic interventions Exercise: As per VA 2022 guidelines, advise practicing exercise (such as yoga, tai chi, qi gong, resistance, and aerobics) as an adjunct in patients with MDD. B As per APA 2019 guidelines, consider offering exercise monotherapy in adult patients with MDD if psychotherapy or pharmacotherapy is either ineffective or unacceptable. Consider offering yoga if neither exercise nor St. John's wort is acceptable or available. C Bright light therapy: As per VA 2022 guidelines, consider offering bright light therapy in patients with mild-to- moderate MDD with or without a seasonal pattern (formerly seasonal affective disorder). C As per APA 2019 guidelines: https://web.pathway.md/diseases/recOMiCCPIv46TowQ 6/15 6/29/23, 6:18 AM Major depressive disorder Pathway Consider offering bright light therapy in adult patients with MDD if psychotherapy, pharmacotherapy, exercise, and St. John's wort are ineffective, unacceptable, or unavailable. C Consider offering bright light therapy for the treatment of patients with seasonal affective disorder as well as nonseasonal depression. C Bibliotherapy: as per VA 2022 guidelines, consider offering CBT-based bibliotherapy as an adjunct to pharmacotherapy or psychotherapy, or as an alternative when patients are unwilling or unable to engage in other treatments. C Herbal products: As per VA 2022 guidelines, consider offering standardized extract of St. John's wort as monotherapy in non-pregnant and non-breastfeeding patients with mild MDD preferring herbal treatments to first-line psychotherapy or pharmacotherapy. C As per APA 2019 guidelines, consider offering St. John's wort monotherapy in adult patients with MDD if psychotherapy or pharmacotherapy is either ineffective or unacceptable. C Acupuncture: As per VA 2022 guidelines, insufficient evidence to recommend for or against acupuncture as an adjunct in patients with MDD. I As per APA 2019 guidelines: Consider adding acupuncture to antidepressant therapy in adult patients with MDD if psychotherapy, pharmacotherapy, exercise, and St. John's wort are ineffective, unacceptable, or unavailable. C Insufficient evidence to recommend acupuncture monotherapy in patients with MDD. I 6. Therapeutic procedures Electroconvulsive therapy: As per VA 2022 guidelines, offer electroconvulsive therapy, with or without psychotherapy, in patients with severe MDD and any of the following conditions: catatonia psychotic depression severe suicidality history of a good response to electroconvulsive therapy need for rapid, definitive treatment response on either medical or psychiatric grounds risks associated with other treatments are greater than the risks of electroconvulsive therapy for the specific patient (co-occurring medical conditions make electroconvulsive therapy the safest MDD treatment alternative) history of poor response or intolerable adverse effects to multiple antidepressants. A As per APA 2010 guidelines: https://web.pathway.md/diseases/recOMiCCPIv46TowQ 7/15 6/29/23, 6:18 AM Major depressive disorder Pathway Offer electroconvulsive therapy as a treatment choice in patients with severe MDD not responding to psychotherapeutic and/or pharmacological interventions, particularly in patientd with significant functional impairment or not responding to numerous medication trials. A Identify conditions requiring modifications in electroconvulsive therapy technique (such as cardiac conditions, hypertension, CNS lesions) when electroconvulsive therapy is used to treat MDD in patients with a co-occurring general medical condition. A Transcranial magnetic stimulation: consider offering repetitive transcranial magnetic stimulation for treatment of patients showing partial or no response to 2 adequate pharmacologic treatment trials. C 7. Specific circumstances Pediatric and adolescent patients (evaluation): obtain evaluation for depression in patients screening positive on the formal screening tool (either as part of universal or targeted screening), presenting with any emotional problem as the chief complaint, or when depression is highly suspected despite a negative screen result. A Show 2 more Pediatric and adolescent patients, counseling and treatment plan: As per AAP 2018 guidelines: Consider offering a period of active support and monitoring before starting evidence-based treatment in patients with mild depression. C Offer scientifically tested and proven treatments (psychotherapies, such as CBT or interpersonal psychotherapy for adolescents, and/or antidepressant treatment, such as SSRIs) whenever possible and appropriate to achieve the goals of the treatment plan. A As per AAP 2018 guidelines, educate and counsel families and patients about depression and options for managing the disorder. Discuss the limits of confidentiality with the adolescent and family. B Show 2 more Pediatric and adolescent patients (psychotherapy): insufficient evidence to recommend behavioral therapy, cognitive therapy, CBT, family therapy, play therapy, problem-solving therapy, psychodynamic therapy, or supportive therapy for the initial treatment of pediatric patients with depressive disorders. I Show 2 more Pediatric and adolescent patients (pharmacotherapy): insufficient evidence to recommend pharmacotherapy in pediatric patients with depressive disorders. I Show 3 more Pediatric and adolescent patients (management of comorbidities): consider consulting with a mental health specialist in adolescent patients with moderate or severe depression or complicating factors and/or conditions, such as coexisting substance abuse or psychosis. Communicate and agree on appropriate roles and responsibilities for ongoing co-management by https://web.pathway.md/diseases/recOMiCCPIv46TowQ 8/15 6/29/23, 6:18 AM Major depressive disorder Pathway the primary care clinician and mental health clinicians. Ensure that the patient and family are active team members and approve the roles of the primary care and mental health clinicians. C Pediatric and adolescent patients (monitoring): monitor for adverse events during antidepressant treatment (SSRIs). B Show 4 more Pregnant patients, evaluation: As per USPSTF 2019 guidelines, refer pregnant and postpartum females at increased risk of perinatal depression for counseling interventions. B As per APA 2010 guidelines: Assess for the presence of suicidal ideas, homicidal ideas, and psychotic symptoms in patients with depression during the postpartum period. A Assess parenting skills for the infant and for other children in the patient's care. A Pregnant patients, management: As per DoD/VA 2022 guidelines: Offer evidence-based psychotherapy as first-line treatment in pregnant or breastfeeding patients with mild-to-moderate MDD. A Weigh the risk-benefit balance for both mother and fetus when deciding on treatment in patients with a pre-pregnancy history of antidepressant-responded MDD currently being stable on pharmacotherapy. A As per APA 2010 guidelines, obtain a careful assessment of the benefits and risks of available treatment options for the patient and the fetus in pregnant patients (or patients contemplating pregnancy). A Show 6 more Elderly patients (management of minor depression): Consider offering any of the following options in patients with subthreshold or minor depression: CBT (internet) for subthreshold depression CBT (individual) and usual care for minor depressive disorder CBT (group) and usual care for treating minor depressive disorder combination of CBT and usual treatment over a combination of talking control (individual) and usual care in older adult patients with minor or MDD life review course (group) over an educational video in older adult patients with subclinical depression problem-solving therapy (individual) paroxetine. C Insufficient evidence to recommend the following options in patients with minor depression: behavioral bibliotherapy (self-guided) versus usual treatment for subthreshold depression life review therapy (individual) versus usual treatment for subclinical depression. I Elderly patients, management of major depression: https://web.pathway.md/diseases/recOMiCCPIv46TowQ 9/15 6/29/23, 6:18 AM Major depressive disorder Pathway As per DoD/VA 2022 guidelines, consider offering first-line psychotherapy in 65 years old patients with mild-to-moderate MDD. take into consideration patient preference and additional safety risks of pharmacotherapy when making this decision. C As per APA 2019 guidelines, offer any of the following options as initial treatment in older adult patients with depression in the context of shared decision-making with the patient: either group life review treatment or group CBT (either alone or added to usual care) combined pharmacotherapy and interpersonal psychotherapy; use a second-generation antidepressant due to the reduced risk of side effects. A Show 2 more Elderly patients (secondary prevention of major depression): Offer any of the following options in older adult patients with a history of depression: combination interpersonal psychotherapy and pharmacotherapy combination supportive care and pharmacotherapy. A Show 2 more Elderly patients (patients with cognitive impairment): Consider offering any of the following options in patients with MDD or minor depression in the context of cognitive impairment or dementia: problem-solving therapy (individual) in older adult patients with MDD and executive dysfunction problem-solving behavioral therapy (individual) or pleasant events behavioral therapy (individual) for minor or MDD in older adults with dementia. C Show 2 more Elderly patients (patients with other comorbidities): Consider offering the following options in patients with both depression and an indicated complicating factor: combination of CBT (individual) and usual care for minor or MDD with T2DM or COPD multicomponent intervention (individual) for treating symptoms of depression in temporarily homebound African American adults coping improvement (group) rather than psychotherapy on request (individual) in older adults with mild-to-severe depressive symptoms and human immunodeficiency virus. C Patients with subclinical depression: consider offering psychotherapy (including both CBT and non-cognitive-behavioral therapy psychotherapies such as interpersonal counseling, problem- solving therapy, life review therapy) in adult patients with subclinical depression. C Patients with relationship distress: As per VA 2022 guidelines, consider offering couples-focused therapy in patients with mild-to- moderate MDD and significant relationship distress. C As per APA 2019 guidelines, consider offering problem-focused couples therapy in adult patients with depression experiencing relationship distress, if a recommended treatment is not acceptable or available. C Patients with cancer (evaluation): obtain regular screening and assessment for depression (such as feeling down, depressed, or hopeless; having little interest or pleasure in doing things; https://web.pathway.md/diseases/recOMiCCPIv46TowQ 10/15 6/29/23, 6:18 AM Major depressive disorder Pathway thoughts of suicide) in all patients with cancer in all phases of illness. B Show 3 more Patients with cancer, management: As per ASCO 2023 guidelines, provide culturally informed and linguistically appropriate information to patients with cancer and moderate-to-severe depressive symptoms and patient- identified caregivers, family members, or trusted confidants. Consider including the following in the provided information: the commonality (frequency) of depression, common psychological, behavioral, and vegetative symptoms, signs of symptom worsening, and indications to contact the medical team (with the provision of contact information). B Show 3 more As per ESMO 2023 guidelines, offer a combination of psychotherapeutic and psychopharmacological modalities for the treatment of depression in patients with cancer. A Show 4 more 8. Patient education Patient education: provide education about the symptoms and treatment of MDD in language readily understandable to the patient. Consider providing education about the illness, its effects on functioning (including family and other interpersonal relationships), and its treatment with the patient's permission, family members, and others involved in the patient's day-to-day life. A Show 5 more 9. Follow-up and surveillance Assessment of treatment response: obtain careful monitoring of response to treatment. Obtain continued monitoring of co-occurring psychiatric and/or medical conditions to develop and refine the treatment plan. A Show 2 more Enhancing treatment adherence: assess and acknowledge potential barriers to treatment adherence including lack of motivation or excessive pessimism due to depression, side effects of treatment, problems in the therapeutic relationship, or logistical, economic, or cultural barriers to treatment, and collaborate with the patient to minimize the impact of these potential barriers. A Show 2 more Discontinuation of treatment: taper the medication over the course of at least several weeks when discontinuing pharmacotherapy. A Show 4 more 10. Quality improvement Cultural considerations: https://web.pathway.md/diseases/recOMiCCPIv46TowQ 11/15 6/29/23, 6:18 AM Major depressive disorder Pathway Assess the impact of language barriers, as well as cultural variables influencing symptom presentation, treatment preferences, and the degree to which psychiatric illness is stigmatized in the assessment and treatment of MDD. A Recognize that ethnic groups may differ in their metabolism and response to antidepressant medications. B Clinical findings Symptoms Past medical history Agitation AUD Anxiety Burning mouth syndrome Back pain Chronic pain Decreased energy Covid-19 infection Fatigue Depression Inappropriate guilt Diabetes mellitus Insomnia Dysthymic disorder Irritability Folate deficiency Loss of appetite HF Memory impairment Hypothyroidism Restlessness Menopause Sleeping disorder Myocardial infarction Slow movements Spinal cord injury Slow thinking Stroke Somnolence Substance use disorder Suicidal ideation TBI Trouble concentrating Neurological exam Weight gain Weight loss Mood alteration Social history Child abuse Domestic violence Negative life event Likelihood Ratios Pertinent positives The following findings increase the probability of major depressive disorder in adults. 15 https://web.pathway.md/diseases/recOMiCCPIv46TowQ 12/15 6/29/23, 6:18 AM Major depressive disorder Pathway Finding LR+ Value Pertinent negatives Fullfilled PHQ-9 score ( 10) ( 10) 4.9-7.3 The following findings decrease the probability of major depressive disorder in adults. 15 Fullfilled PRIME-MD ( 1) ( 1) 2.6 (2.1-3.2) Finding LR- Value PHQ-9 score < 10 0.02-0.14 PRIME-MD score = 0 0.15 (0.08-0.28) Studies 2023 iCBT (secondary analysis, guided iCBT vs. usual treatment) In university students with anxiety and/or depression, clinician-guided iCBT was superior to treatment as usual with respect to joint remission of anxiety and depression at 3 months. Corina Benjet et al. JAMA Psychiatry. 2023 Jun 7. 2023 iCBT (secondary analysis, guided iCBT vs. self-guided iCBT) In university students with anxiety and/or depression, clinician-guided iCBT was superior to self- guided iCBT with respect to joint remission of anxiety and depression at 3 months. Corina Benjet et al. JAMA Psychiatry. 2023 Jun 7. Show 5 more References 1. John R McQuaid, Andrew Buelt, Vincent Capaldi et al. The Management of Major Depressive Disorder: Synopsis of the 2022 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline. Ann Intern Med. 2022 Sep 20. Open 2. John R. McQuaid, Elizabeth H. Lin, Jacques P. Barber et al. APA CLINICAL PRACTICE GUIDELINE for the Treatment of Depression Across Three Age Cohorts. APA. 2019. Open 3. Joffres M, Jaramillo A, Dickinson J et al. Recommendations on screening for depression in adults. CMAJ. 2013 Jun 11;185 9 775 82. Open 4. L Grassi, R Caruso, M B Riba et al. 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