AUTHOR
Ellen Feldman, MD, Altru Health System, Grand Forks, ND
PEER REVIEWER
Steven M. Winograd, MD, FACP, Clinical Assistant Professor of Emergency Medicine, Mt. Sinai Medical School and Bon Secours Hospital, New York
EXECUTIVE SUMMARY
More than half of the 8 million depression-related provider visits in the United States occur in a primary care setting. The primary care provider (PCP) is the most likely practitioner responsible for the detection and management of the disorder.
- The World Health Organization has identified depression as the leading cause of disability worldwide, affecting 4.4% of the global population. In the United States, the 12-month prevalence of depression is 10.4% and the lifetime prevalence is 20.6%.
- Those most at risk include women, younger adults (vs. those older than age 65 years), white adults, and Native Americans.
- Diagnosis classifies depressive episodes as mild, moderate, or severe based on the number, type, and severity of symptoms, but, most importantly, on the degree of functional impairment.
- The U.S. Preventive Services Task Force recommends depression screening for all adults during PCP visits, as long as a diagnostic evaluation follows a positive screen and follow-up is available. The Patient Health Questionnaire is the most common screening instrument used.
- Depression is a major risk factor for completed suicide, suicide attempts, and self-harm. A 2017 study revealed about one-half of adults completing suicide had contact with a PCP within a month before death, and 80% had such contact in the year preceding suicide.
- Treatment involves managing depression as a chronic condition. Treatment options include psychotherapy, pharmacotherapy, and adjunct interventions.
Emerging from a complex interaction of biologic and psychosocial factors, depression can be challenging to recognize, treat, and manage. There are no pathognomonic signs. Age, personality, and cultural norms influence the clinical presentation. Complaints often are vague and challenging to quantify. Ironically, the hopelessness and despair that are part of the disorder itself may interfere with compliance and treatment.
Slightly more than one-half of the 8 million depression-related provider visits that occur yearly in the United States are in a primary care setting. Thus, although depression clearly is a disorder of mental health, primary care providers (PCPs) are most likely to be responsible for the detection and management of this disorder.1 Building an in-depth understanding of depression, including diagnostic criteria, comorbidities, disease course, and, most importantly, recognition of the effect of symptoms on an individual, empowers providers to identify and manage this common disorder.
Part of the challenge of management is that the natural course of depression is chronic and recurrent. Frequently occurring comorbid conditions, including other disorders of mental health, substance abuse, and physical disorders, complicate the disease course. Stigma, shortage of mental health support, and lack of community resources also are major obstacles in efforts to combat depression. Patients may present with somatic symptoms and may be hesitant to discuss underlying feelings related to depression, such as worthlessness, hopelessness, and suicidal thoughts.1,2 Applying principles developed for the management of chronic disease (such as diabetes, obesity, or hypertension) to depression is appropriate, and enables the evaluation and adjustment of treatment over time.3
The goal of this article is to provide the PCP with up-to-date guidelines regarding depression diagnosis, treatment, and management. The term “depression” will broadly refer to major depressive disorder (MDD) as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM 5)4 and/or the International Classification of Diseases, 11th revision (ICD-11).5 Both of these diagnostic tools contain symptom lists, but it is crucial to understand that the treatment of depression does not rely simply on checking off symptoms; treatment and management decisions hinge on evaluating and minimizing the degree of functional impairment from symptoms.4,5 A comprehensive history and physical exam, and an ongoing patient-provider relationship with open communication, thus, are critical to diagnosis, treatment, and long-term management.1-3
This article begins with a brief discussion of the history of depression in the Western world. Moving to modern times, a discussion of epidemiology reveals the scope of this disorder. An overview of diagnosis, risk factors, common comorbidities, and evidence-based treatments follows.
Historical Overview
Tablets from the Mesopotamian era and scrolls from ancient Egypt depict symptoms of depression. The treatment involved priests and exorcism, since mental illness was believed to be a sign of demonic possession.6
By the 5th century B.C., Hippocrates developed the idea of depression stemming from imbalances within the body and defined “melancholia” (an excess of black bile) as an “aversion to food, despondency, sleeplessness, irritability, restlessness” — a descriptive classification of symptoms that could be at home in our modern-day DSM. Treatments included bloodletting, bathing, exercise, and diet.6,7
Religious concepts of mental illness dominated scientific thinking during the Middle Ages; intervention for depressive symptoms reverted back to exorcism of “demons.” The concern that mental illness was contagious gave rise to early “lunatic” asylums.6,7
The Renaissance ushered in new ways of thinking about mental illness. In the 1600s, Thomas Willis, the “father” of neuroscience, moved the discussion of the etiology of depression away from an imbalance of humors or bodily fluids toward a problem within the brain.8 Robert Burton, in his 1621 Anatomy of Melancholy, described psychosocial contributors to depression and recommended treatments, including music therapy, exercise, diet, and socialization.9
Work on understanding the causes of depression continued into the 18th and 19th centuries. Biological theories conflicted with ideas that the environment and character were causative factors. Treatments included spinning stools to a form of near drowning to electrical shock. Institutions became popular as a result of the misconception that unchangeable character flaws were the root of depression.6,7
By the early 1900s, the theories of Sigmund Freud and psychoanalysis rose to the forefront of treatment; unfortunately, this was not curative for severe depression, and some practitioners turned to lobotomies for a final effort at a cure. In the 1950s, with a fortuitous discovery of the antidepressant properties of monoamine oxidase inhibitors and the advent of tricyclic antidepressant medications, the theory of brain chemistry involvement in depression gained prominence. Despite the efficacy of these medications, serious side effects limited their use. It was not until 1987 and the introduction of the modern-day selective serotonin reuptake inhibitors, such as fluoxetine and sertraline, that antidepressant prescriptions soared.10
With the 21st century came a blended, biopsychosocial model of the etiology of depression. Antidepressants, psychological treatments, and psychosocial and biological interventions now hold prominent positions in the armamentarium developed to combat this disorder. Procedures such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMR) show promise when other treatments are not effective.
Unfortunately, the stigma of the past has not dissipated entirely, leaving the majority of more than 264 million people with depression worldwide without proper care.10,11
Epidemiology
The World Health Organization (WHO) notes that depression is the leading cause of disability worldwide, affecting 4.4% of the global population. Mortality also is a concern; depression is associated with an increased risk of suicide and is linked to worse medical outcomes and fatalities when comorbid with cardiovascular diseases.11,12
The availability of modern medicine has not shielded the U.S. population from the disability associated with depression. Studies show that those with depression miss work at about twice the rate of persons without this disorder. With higher medical costs and disrupted work lives, the economic burden of depression rose from $173 billion in 2005 to $210.5 billion in 2010, about a 20% increase.13
Most studies indicate that the prevalence rates for depression are about one and a half to two times greater in women than in men; that adverse circumstances, such as poverty and trauma, affect the expression of depression; and that comorbidity between depression and other chronic conditions complicates the disease course. Genetics play a role in this disorder, with estimates of the heritability of depression around 37%. This rate is significantly less than other disorders of mental health, and points to the effect of environmental stressors on the emergence of depression.14,15
In the United States, a comprehensive national survey in 2012-2013 of more than 36,000 adults revealed a 10.4% 12-month prevalence of depression and 20.6% lifetime prevalence. Most of these episodes were rated moderate to severe; 13% of the respondents with severe episodes noted a history of a suicide attempt. About 70% of the respondents who endorsed symptoms reported receiving a form of treatment for depression. The highest rates of depression were in younger adults, as opposed to those older than age 65 years. Consistent with other studies, prevalence varied with race, with white adults and Native Americans being most at risk vs. African-American, Hispanic, and Asian American adults.16
Recurrent episodes, even with treatment, appear to be part of the natural course of depression. Studies find a 40% to 60% rate of recurrent depression after recovery from an initial depressive episode. The likelihood of recurrence increases with each subsequent episode, with the risk of recurrence highest in the months following recovery. Prevention efforts remain one of the most challenging goals in management of this disorder.17
As alluded to earlier, there appears to be an important bidirectional relationship between depression and other chronic conditions, with a multiplicative effect on morbidity when depression is comorbid with another disorder. Higher risks of depression are seen in persons with a variety of conditions, including cardiovascular disease, diabetes, end-stage renal disease, neurologic disorders, other disorders of mental health (especially anxiety disorders), and substance abuse disorders. In some of these cases, depression may be a risk factor itself for development of the comorbid condition. In all cases, recognizing the comorbidity is highly important in effective treatment.18
Diagnosis: Criteria, Screening, and Risk Factors
A diagnosis of depression follows guidelines from DSM-5 or ICD-11.4,5 There have been no definitive studies recommending one method over the other; clinicians are free to use either to diagnose depression. Typically, in the United States, clinicians use the DSM-5 to diagnose, but submit billing codes based on ICD-11. Familiarity with both systems eases this process. Tables 1 and 2 present diagnostic criteria from each system.19
Table 1. Criteria for DSM-5 Major Depressive Disorder4 |
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Five or more symptoms, including either depressed mood and/or loss of interest and/or loss of energy, are present during at least two weeks. Symptoms result in a change in functioning, are not better explained by another psychiatric disorder, are not the result of the effects of a substance or pharmaceutical agent, and are not caused by another medical condition. There has never been a hypomanic or manic episode, and current symptoms do not meet criteria for a mixed episode. |
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1. Depressed mood most of the day (patient report or noticed by others) 2. Decreased interest or pleasure in most activities, most days (patient report or noticed by others) 3. Significant change in body weight or appetite (increase or decrease) 4. Insomnia or hypersomnia most days 5. Psychomotor agitation or retardation most days (must be observable by others) 6. Profound fatigue or energy loss most days 7. Profound feelings of worthlessness or guilt (may be delusional) most days 8. Decreased ability to concentrate or make decisions most days (patient report or noticed by others) 10. Recurrent thoughts of death, suicidal ideation or plan/attempt |
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DSM-5: Diagnostic and Statistical Manual of Mental Disorders, 5th edition |
Table 2. Criteria for ICD-11 Depressive Disorder5 |
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For at least two weeks, almost daily depressed mood or decreased interest in activities is present. Other accompanying symptoms may include those listed here. No history of manic, hypomanic, or mixed episode. |
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1. Concentration difficulties 2. Profound feelings of worthlessness or inappropriate guilt 3. Hopelessness, recurrent thoughts of death, suicidal ideation 4. Changes in sleep and/or appetite 5. Reduced energy and/or increased fatigue 6. Psychomotor retardation or agitation |
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ICD-11: International Classification of Diseases, 11th revision |
The similarities between the two systems outweigh the differences. To diagnose depression, both systems require the presence of at least one key symptom: depressed mood or loss of interest/energy. Both specify that these must be present for at least two weeks and in sufficient severity to interfere with daily functioning. Additionally, DSM-5 specifies at least another five out of nine related symptoms be present, while ICD-11 notes other accompanying symptoms are present (but does not quantify these). In general, a person diagnosed with depression using DSM-5 criteria will qualify for ICD-11 diagnosis as well, but the converse is not necessarily true.4,5
Each system classifies depressive episodes as mild, moderate, or severe based on the number, type, and severity of symptoms, but, most importantly, on the degree of functional impairment. For example, patients with mild depression may experience five or six symptoms but have stable functioning, while a patient with severe depression typically will describe more symptoms, but, more importantly, will experience significant interference with daily functioning. Understanding the degree of functional impairment or interference with daily life involves an element of subjectivity, is heavily dependent on history from the patient or other reporters, and may need more than one appointment.4,5,19
Introducing J.T.
J.T., a healthy, multiracial 38-year-old male on no regular medication comes in to see “if I need something for sleep.” He states his sleep pattern has changed over the past six to eight months, and attributes this to more responsibility at work and the recent birth of a second child. He reports more difficulty getting to sleep, a decrease in his usual exercise routine, a five- to seven-pound weight gain, and a decrease in motivation, saying, “Everything feels like it is so much effort.” He states his wife thinks he is less interested in interacting with her and the family, and he admits to less patience with her and the children.
Numerous studies have confirmed what many PCPs know to be true: Recognizing depression in a primary care setting, especially in a patient with comorbid conditions, is challenging. Most patients do not come in with a chief complaint of depressed mood, but instead will report less-specific symptoms, such as decreased energy, general body aches, or digestive concerns. Somatic complaints (such as insomnia, headaches, or back pain) also are a likely reason for a visit. Older adults are even less prone to report concerns about mood but will present with complaints regarding memory or cognition. It is usually toward the end of the visit, if at all, that concerns about depressed mood arise. Screening tools for depression, self-administered to patients during routine visits to a PCP, have emerged as a partial solution for this problem of identifying depression.20
Unfortunately, no general agreement exists on the efficacy of screening tools for depression or how often screening should occur. Concerns about screening revolve around several issues, including use of resources, lack of clear evidence of benefit to patients from screening, and suggestion of overdiagnosis and overuse of antidepressants because of such screens.19
The U.S. Preventive Services Task Force (USPSTF) recommends depression screening for all adults during PCP visits, as long as a diagnostic evaluation follows a positive screen, and follow-up is available. The Institute for Clinical System Improvement recommends a different approach, stating to reserve screening for patients with high-risk factors or presentation suggestive of depression. Standards vary globally, with recommendations in the United Kingdom leaning toward screening only patients with a history of depression or physical illness. In Canada, updated guidelines recommend screening only patients with a history of depression or suggestive symptoms.21
A 2005 systematic review of investigations looking at the benefits of screening in non-mental health settings found a minimal effect on diagnosis or management of depression from screens.22 In 2013, a randomized trial comparing screening for depression and a control group found no difference in detection of depression between the two groups.23 However, when linking screens with follow-up, the picture changes. Recent multisite studies have shown that patients report better control of depressive symptoms and reduction in symptom severity over 12 months when comparing screening and structured follow-up to collaborative care or care as usual. Considering the evidence for and against depression screening, Ferenchick et al, in a 2019 comprehensive review of depression in primary care, noted that screening alone is not effective in addressing or detecting depression, but that significant improvement in outcomes arises when “primary care practices can support accurate diagnosis, effective treatment, and appropriate follow-up.” Further recommendations include screening adult patients at least once, and then considering the presence or absence of risk factors, including life events, to initiate a repeat screen at a subsequent visit.19
The screening instrument used most often to detect and follow the treatment of depression in the PCP office is the Patient Health Questionnaire (PHQ). Both the PHQ-2 (a two-item questionnaire) and the PHQ-9 (a nine-item questionnaire) are free and self-explanatory.24,25 Each questionnaire allows one response per question ranging on a scale from “not at all” to “nearly every day.” Scores reflect the likelihood of depression, with a score of 5 to 27 representing mild to severe depression on the PHQ-9 and a score of 3 (out of 6) representing depression on the PHQ-2. Many offices combine the two, asking patients to fill out a PHQ-9 if the PHQ-2 is positive; however, there is limited and conflicting evidence that this practice is useful in diagnosis or assessing the response to treatment. Diagnostic specificity and sensitivity of these two scales vary, with the PHQ-9 having a more established record of reliability. In general, the best practice is to use a screening tool for depression in conjunction with a comprehensive history and physical — never depend on a depression screen alone for the diagnosis of depression.19,24,25
When J.T. fills out the PHQ-2, he checks off “several days” regarding question one (“Little interest or pleasure in doing things”) and “more than half the days” in response to question two (“Feeling down, depressed or helpless”), totaling a score of 3 — the threshold for depression on this screen. When his PCP asks him about these responses, he says, “Actually, most of the time I feel OK — it’s just hard feeling torn between my family and work … sometimes it feels like there is no way to please everyone.”
The results of the screen serve as a natural transition to discuss depression and risk factors during the clinical interview. Open-ended, empathic statements (for example, “It is hard to feel that way”) help build trust and establish a clinical alliance.19,26
Risk factors play a significant role in a diagnostic evaluation. The greatest single risk factor for a subsequent episode of depression is a history of a past episode. A history of other mental illnesses, substance use, family history of depression or suicide, chronic medical conditions, recent stressful life events, unemployment, and domestic abuse all raise the risk of depression and may serve to direct a diagnostic interview.19,26
Differential Diagnosis and Comorbidity
There are depressive disorders that do not meet full criteria for MDD under DSM-5 or depressive disorder under ICD-11. These include disruptive mood dysregulation disorder, premenstrual dysphoric disorder, unspecified depressive disorder, and a form of low-level persistent depression aptly named persistent depressive disorder. Consulting the DSM-5 is helpful when a patient presents with symptoms of depression, without meeting full criteria for MDD.4
Patients with bipolar disorder often present with depressed or low mood. To clarify diagnosis and prevent treating a patient with bipolar disorder with potentially contraindicated antidepressants, both the DSM and ICD criteria caution providers to be on the lookout for symptoms of mania or hypomania predating the depressive episode. Asking about time with unusual elevation of mood, irritability, and/or poor sleep combined with excessive energy is helpful in eliciting a history suggestive of mania. If such a history is positive, treatment will lean toward mood stabilizing agents and may require a referral to a mental health specialist.19,27
Other psychiatric conditions, especially anxiety and substance use disorders (SUD), frequently co-occur with depression. Up to 50% of depressed patients may have comorbid anxiety; when depression presents with anxiety, remission is more difficult to achieve. Periodic screening of patients with depression, especially in patients not responding well to treatment, with an instrument such as the Generalized Anxiety Disorder Scale (GAD-2 or GAD-7) may help uncover an underlying anxiety disorder.29 These screens have better negative predictive value than positive predictive value and, as with all screens, are best used in combination with a diagnostic interview.19,28
The prevalence of comorbidity between depression and SUD ranges from 8.6% to 25%. In a study of 2,500 outpatients with depression, SUD risk was significantly higher in younger males with an early age of depression symptom onset and high functional impairment. Integrating nonjudgmental screening questions regarding substance use in patients with depression often leads to a more accurate diagnosis, which in turn permits targeted treatment decisions.19,30
There is a symptom overlap between some medical conditions and depression. Common disorders, such as thyroid disease and anemia, may present with the poor energy and fatigue seen in depression. Neurologic disorders, such as Parkinson’s disease, multiple sclerosis, and dementia, may present with low mood and cognitive changes, similar to a picture seen in patients with depression. A careful history, physical exam, and diagnostic lab testing is helpful in distinguishing these conditions. If there have been changes in medications, examining the time course of symptom onset and functional changes is particularly relevant. A diverse range of pharmaceutical agents, including beta-blockers, some oral contraceptives, and steroids, may precipitate depressive symptoms.19,23,26
J.T. notes that he has never been depressed, does not believe he is depressed now (“just stressed”), and does not report a history of depression in his family, but says, “We wouldn’t talk about it if there was … my family believes in a stiff upper lip.” He states his grandparents on both sides were heavy drinkers, “so I don’t touch the stuff.” However, when asked what he has done about his sleep problem, he notes that he has been using marijuana one to three times weekly to get to sleep, since “nothing else helped.” His physical exam is unremarkable except for the weight gain and mild elevation of systolic blood pressure. He denies suicidal thinking or intention, but says there are times he thinks, “Life is just too hard to keep going like this — something has to change.”
Evaluating Suicidal Risk
As may be expected, depression is a major risk factor for completed suicide, suicide attempts, and self-harm. A 2017 study revealed close to one-half of adults completing suicide had contact with a PCP within a month before death, and 80% had such contact in the year preceding suicide.31 Patients may be hesitant to express thoughts about suicide directly, but often will respond to open-ended queries. Asking patients with depression or depressive symptoms about suicidal thoughts, plans, or intentions may open a discussion. Screens such as the Columbia Suicide Severity Rating Scale (C-SSRS) can be useful, but as with screens for depression, cannot replace a careful diagnostic evaluation or stand alone in representing suicidal thinking.19,32
Refer patients with high-risk factors and suicidal intention to a specialist. Regional variation in mental health specialist availability ultimately may determine referral and consultation patterns. There is growing evidence that collaborative care models, with a team led by the PCP and containing mental health professionals, including psychiatry and case management, leads to efficient and effective care for more complex, higher-risk patients with depression. Telemedicine consultation also has shown evidence of efficacy and can assist in bringing specialty care to previously underserved communities. Regardless of the manner of delivery, it is useful for the PCP to have a strong working relationship with professionals in the mental health community. In addition, providing patients with information about local support groups and services, such as suicide hotlines, provides an additional safety net for this population.19,33,34
Treatment
As previously noted, the course of depression often is chronic and recurrent. Current recommendations are to manage depression in primary care as a chronic condition, with follow-up of symptoms, side effects, treatment compliance, and treatment modification as needed to achieve the best outcome. Treatment outcomes include multiple interrelated possibilities: response, remission, or recovery. Response is achieved when intensity or frequency of symptoms is reduced 50% from baseline; remission is a return to pre-baseline functioning with minimal symptoms; recovery, which is the universal goal, is a state of remission lasting longer than two months.34
Relapse occurs following any degree of remission before a recovery, while recurrence suggests a new episode of depression. Research suggests 10% to 15% of primary care patients with depression will have a chronic course without clear remission, and that greater dysfunction at baseline may be predictive of such a course. With a > 40% recurrence rate of depression after an initial episode, treatment is aimed at both immediate symptom relief and longer-term prevention.17,34
Evidence-based treatment for depression in primary care includes the use of specific psychological therapies and/or pharmacological agents. A meta-analysis in 2013, and again in 2017, comparing these interventions for depression in primary care found efficacy for each, but no clear “winner” in the treatment of depression. Not surprisingly, treatment guidelines vary. Treatment guidelines in the United Kingdom and New Zealand advise psychological therapy alone for mild to moderate depression while reserving medication treatment (combined with psychotherapy) for more severe cases. In the United States, guidelines from the American College of Physicians and the Institute for Clinical Systems Improvement recommend either medication or psychotherapy as first-line treatments. All of the guidelines emphasize that severity of functional impairment, as measured by the effect of symptoms on everyday life, should be the primary factor in defining the severity of depression (as opposed to the number of symptoms or other factors).34,35
Psychotherapy
Cognitive behavioral therapy (CBT), a highly structured talk therapy, delivered individually or in a group setting, has a track record of evidence-based studies showing efficacy over treatment as usual in depression. Other, less well-studied therapies (such as problem solving and interpersonal therapies) may have equal or greater effect, but firm conclusions await more research and head-to-head investigations. Home or office-based treatments, including guided self-help and computerized CBT, have limited efficacy, with more quality studies needed to clarify if either can play a more robust role in the treatment of depression. Generic “psychological counseling” has suggestive evidence of an effect similar to CBT.34
Mindfulness-based cognitive therapy (MBCT), an eight-week, group-based skill-building program with elements of CBT, has evidence for use specifically in depression prevention. Although studies confirming its efficacy and mechanism of action continue, the American Psychological Association endorses MBCT as a viable treatment to prevent the relapse of depression. Many guidelines for depression prevention among high-risk patients worldwide incorporate this therapy as well. The availability of groups may limit access to MBCT; however, studies are looking into self-help MBCT and virtual dissemination.36
Investigations looking at factors influencing the success of therapy have pointed to the relationship between the patient and the therapist, as well as the patient’s expectation, as highly significant, perhaps even more so than the type of therapy. Interestingly, the patient’s expectation of the response to pharmaceutical intervention in depression also plays a role in predicting the response when medication is used for depression. This is relevant to the PCP, especially when deciding about treatment direction, type of intervention, and when evaluating treatment response. Involving a patient in treatment decisions about referral to therapy and/or medication opens a door to understanding the patient’s view and any concerns a patient holds about specific forms of treatment.17,34
J.T. repeats that he does not think he has depression. He says he is worried about the marijuana use (especially with young children in the household) and would rather have a sleep medication than continue his current pattern of use. He expresses surprise that the insomnia, poor motivation, mild emotional distancing, and mild irritability he describes all could be a result of depression. He does not want to see a therapist, saying, “I don’t think I would have anything to say.” He is open to discussing medication for these symptoms as long as the medication helps with sleep. He thinks if he could sleep better he would have more energy, less irritability, and a better mood overall.
Medications
Selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), norepinephrine and dopamine reuptake inhibitor (NDRI), or tricyclic antidepressant (TCA)?
Commonly referred to by acronyms indicating the mode of action, it is easy to be lost in the alphabet soup representing more than 30 Food and Drug Administration (FDA)-approved antidepressants. Although specific neurochemical targets vary, all antidepressants work by initially increasing serotonin and/or norepinephrine availability. A large 2018 meta-analysis looking at the efficacy of antidepressants in primary care practices found significant effect size for antidepressants over placebo. The choice of an agent involves obtaining patient input regarding target symptoms (for example sleep, cognitive functioning, appetite), expected tolerance of specific side effects, interactions with other medications, and affordability or insurance restrictions.34,37,38
All antidepressants have a delay in response. Recommendations from large-scale studies, including the landmark Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, are to use a stepped approach, with frequent re-evaluation and sequential treatment adjustments. A typical scenario is to evaluate the tolerance of the antidepressant at weeks 1 to 2 and look for response by week 3 or 4. If there is no response at all, consider increasing the dose or switching to a different agent. Remember that some individuals are slow responders, so wait longer for a response if there is any suggestion of effect during this initial period.34
A strategy from STAR*D is to augment the treatment with an antidepressant from a different class and/or with talk therapy by week 12.34
If two antidepressants are tried (from the same or from different categories) singularly or in combination, at adequate doses for adequate time, and there remains no response, it is reasonable to seek consultation with a specialist.
With multiple studies showing a high rate of noncompliance with antidepressant treatment, it also is advisable to check medication compliance, as well as use of other pharmaceuticals influencing mood. Finally, throughout each step, consider and address lifestyle factors that could impede progress.17,34,37
Tricyclic Antidepressants
Because of adverse cardiovascular side effects, significant anticholinergic effects, and lethality in overdose, TCAs, or the first-generation antidepressants, are not used as commonly for depression as the other agents. Given the significant sedating side effects, agents such as nortriptyline still play a role in the treatment of insomnia associated with depression.34
Serotonin Reuptake Inhibitors
Serotonin reuptake inhibitors include SSRIs, such as fluoxetine and citalopram; SNRIs, such as duloxetine, venlafaxine, and desvenlafaxine; and serotonin antagonist and reuptake inhibitors (SARIs), such as trazodone. SSRIs are the most common antidepressant agents used in the United States and globally (although the popularity of the specific type of SSRI varies regionally).
Common, well-tolerated side effects include gastrointestinal disturbance and headache. Other side effects include sexual dysfunction and weight gain. The risk of abnormal clotting and bleeds is increased with all of these agents and is potentiated when combined with nonsteroidal anti-inflammatory drugs (NSAIDs) and anticoagulants.34,39
Atypical Antidepressants
Atypical antidepressants include bupropion, an NDRI; and mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA). Newer agents include vilazodone, a serotonin partial agonist reuptake inhibitor (SPARI).34
After discussion, J.T. is agreeable to starting an antidepressant and stopping marijuana while seeing if the medication helps with sleep eventually. He is concerned about the potential sexual side effects with any SSRI, and more interested in bupropion because there is less likelihood of such a side effect. His PCP is concerned about the activation potential of bupropion interfering with his sleep and asks him first to try fluoxetine 10 mg and return for re-evaluation in two weeks. J.T. asks, “If I start this medication, how long do I stay on it?”
Clinical Pearls Regarding Antidepressants
Stopping an Antidepressant
Findings from a 2020 study indicate that, as the prevalence of depression in U.S. adults increased from 6.1% in 1996 to 10.4% in 2015, the proportion of diagnosed patients treated with antidepressants rose from 52.2% to 70%. Additionally, this study noted a substantial increase in the use of long-term (more than five years) single-agent therapy from 13.9% in 1996 to 43.9% in 2015.34,41
In general, this trend holds worldwide. Antidepressant prescriptions are increasing, but longer use of antidepressants is at least part of the reason for this increase. Current research notes an antidepressant course from six to 12 months following remission of the first episode of depression (depending on risk factors) is associated with a 65% decrease in the risk of relapse. To stop an antidepressant, taper slowly after recovery and adequate course, while monitoring for symptom emergence. However, after three episodes of depression, a maintenance dose of medication may be required to achieve remission.34,40,41
Discontinuation syndrome is of particular concern when stopping most antidepressants abruptly, with the onset of symptoms such as irritability, dizziness, electric-shock sensations, and tearfulness within days of the stop date. These symptoms can be self-limiting or can become more substantial and interfere with functioning. Discontinuation syndrome is more likely with medications with shorter half-lives, such as paroxetine and venlafaxine. A gradual tapering of dose over four to six weeks helps prevent this phenomenon.34,41,42
Cytochrome P450 (CYP450)
Most antidepressants interact with the CYP450 system, leading to potential clinically significant drug interactions. Antidepressants with the strongest inhibitory effect on the CYP450 enzymes are fluoxetine (Prozac), fluvoxetine (Luvox), paroxetine (Paxil), and bupropion (Wellbutrin). Take note of the potential for interaction with other prescribed agents and consider dosage adjustments.26
Black Box Warning
The FDA issued a black box warning in 2005 regarding a potential of increased suicidal thoughts in children, adolescents, and young adults taking any antidepressant, especially early in treatment. Although there is controversy regarding the validity of the findings and the usefulness of the warning, clinicians should discuss the warning with patients, weigh the risks of medication treatment, and monitor carefully.43
Serotonin Syndrome
Potentially life-threatening, this syndrome caused by serotonergic drugs (in overdose or as the result of unforeseen interaction) presents from mild to severe with symptoms including agitation, confusion, and tremors, and progressing (when severe) to seizures and coma.1
J.T. calls his PCP’s office several days later, saying he could not bring himself to start fluoxetine. He says he and his wife spoke about restarting a running program, which he thinks will help with sleep. He would like to try the bupropion discussed at the appointment and will keep his follow-up. After discontinuing the fluoxetine, his PCP prescribes bupropion XL 150 mg to be taken every day before noon. At his next appointment, J.T. states, “I feel better. Maybe because our neighbor is watching the kids while my wife and I run together. Maybe the medication. I don’t know. But I have energy in the morning, and work feels more manageable.”
Adjunct Interventions in Treatment of Depression
Studies regarding decreasing social isolation, increasing quality of sleep, encouraging physical activity, and nutritional interventions show promise in the treatment of depression.1,26,34
A Mediterranean-type diet, vitamin supplements, and alpha omega 3 are among the dietary interventions studied in the treatment of depression. The findings are inconsistent, and although there seems to be some promise for these interventions, for the most part the effect size is modest. As the field of nutritional psychiatry advances, studies that are more rigorous may identify specific populations for whom dietary intervention has the most likelihood of success.44
A 2017 meta-analysis looking at 49 prospective studies of physical activity in depression showed a 22% reduced likelihood of developing depression in participants with higher physical activity, but minimal effect on symptom reduction, depression severity, or course of acute depressive episode.34,45
Studies looking at the effect of improving social isolation to address depression are limited and generally of poor quality. A recent large-scale cohort study from the United Kingdom found that low levels of social support significantly factored into higher levels of depression during the 2020 COVID-19 pandemic (along with preexisting mental and physical health conditions, experience of abuse, and lower socioeconomic status).34,46
The effect of sleep on mood is well established. However, more studies are needed to determine if sleep improvement alone can help mitigate depression.34
None of these adjunct measures has shown effect size approaching conventional medications and/or psychotherapy. However, even with established treatment, patients with depression continue to experience residual symptoms resulting in lowered quality of life.
Using a combined approach and integrating these adjunct health and lifestyle measures into an overall treatment plan allows the potential of a more vigorous response to this disorder.34 Consider these measures first-line for patients presenting with mild depression, especially in cases where patients are not interested in either psychotherapy or psychotropic medication. Working with the patient over a defined period toward goals in areas such as improved diet or a more active lifestyle allows a deeper evaluation of depressive symptoms and functioning over time.
If symptoms do not respond or worsen within a few weeks, move to an intervention that is more intensive. However, a patient with few risk factors and mild depression may show symptom remission with better functioning in these areas (sleep, diet, physical activity, and socialization).1,26,34
Special Populations
Older Adults and Medical Comorbidities
Start low, go slow, and closely monitor when initiating pharmacotherapy for depression in older adults. Observational studies in this population point to an increased risk of falls and fractures when using SSRIs and SNRIs.46 Additionally, SSRIs increase the risk of gastrointestinal bleeds and, potentially, the risk of cerebrovascular bleeds.39 Cardiovascular disease and depression have bidirectional comorbidity, with each being an independent risk factor for the other. Current investigations looking at heart rate variability and inflammatory status are homing in on the mechanisms binding these disorders. Antidepressant treatment appears to be particularly beneficial to patients with this specific combination of disorders.48
Antidepressant-induced hepatotoxicity is rare, but possible. A French cohort study of 5 million participants identified 382 serious liver injuries associated with antidepressants, with no differential between the type or class of antidepressant prescribed. However, duloxetine, bupropion, and trazodone are among the antidepressants known to be more likely to be associated with drug-induced liver injury. Obtain baseline liver function tests for patients on polypharmacy or at risk for liver disease. In patients with known liver disease and depression, it is best to use an SSRI and keep doses low.49
In older adults, and all patients with medical comorbidity, the use of polypharmacy increases the risk of side effects and may require dosage adjustments of antidepressants. Nonpharmacologic evidence-based treatment for depression may be useful in many of these cases.34,48
Teens
The 2018 Guidelines for Adolescent Depression in Primary Care address recommendations for the identification, management, and treatment of depression in youth ages 10-21 years.50 Although a full discussion is outside the scope of this article, a few highlights include:
- Screen adolescents for depression yearly using age-specific tools (for example, PHQ-9 modified for teens).
- Identify and monitor patients with high risk (including a family history of depression, a history of adverse events/trauma and other psychosocial stressors, substance abuse, and frequent somatic complaints).
- Evaluate patients who screen positive by conducting a diagnostic interview; include an interview with caregivers.
- Develop a treatment plan with the patient and family, including a safety plan (with an agreement to remove access to guns and other lethal weapons).
- For mild depression, consider active support and monitoring.
- For moderate to severe depression with a comorbidity, consider consultation with a mental health provider.
- For mild to moderate depression requiring intervention, use evidence-based treatment, including SSRI plus CBT (combined treatment is most efficacious).
- When using SSRI or other antidepressants in teens, start low and go slow, with frequent monitoring for adverse events.
Conclusion
J.T., having come for his first follow-up visit, remains on bupropion XL 150 mg, is sleeping without using marijuana, and still is running with his wife. When his PCP sees him at the six-week mark, his score on the PHQ-2 has dropped to a “2” since he checks off that he has “little pleasure in doing things” and times of “feeling down” only a few days over the last two weeks. He wonders if he should stay on the bupropion, stating, “I think what actually helped me the most is that both of our kids are now sleeping through the night.” After a short discussion about his responses on the PHQ-2, antidepressant treatment, and the natural course of depression (which he still is not sure he has), he agrees it makes sense to continue at least a six-month course and to check back with his PCP in another month. He states, “I hope to get the PHQ down to a ‘1’ by the next time I see you!”
J.T.’s story serves to illustrate the multifaceted etiology of this disorder, the importance of consistent follow-up, and highlights the central role of the patient in identifying and prioritizing target symptoms in the treatment of depression. One symptom of depression is a feeling of helplessness; encouraging patients to have an active role in treatment can be a powerful therapeutic intervention and may help compliance by aligning the patient as part of the treatment team.
Mental health expertise and availability is in short supply across the United States. Often, it falls to the PCP to serve as the first-line provider for patients with depression. Recommendations are to screen adults in the PCP practice for depression at least once, and screen adolescents annually. Follow any screens suggestive of depression with a diagnostic interview and comprehensive physical exam. Have a system to evaluate risk factors, and initiate evidence-based treatment that incorporates an understanding of patient preference regarding the type of intervention and which symptoms to target. Connect with local mental health providers and organizations for collaboration and referral. A holistic approach to this chronic disorder involves periodic follow-up and active monitoring; be particularly fastidious about monitoring patients with high-risk factors, including comorbid conditions. Deploy evidence-based and adjunct interventions and align with the patient to adjust the treatment to improve quality of life and achieve remission or recovery from depression over time.
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More than half of the 8 million depression-related provider visits in the United States occur in a primary care setting. The primary care provider is the most likely practitioner responsible for the detection and management of the disorder.
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