NAVIGATING THE LABYRINTH OF DEPRESSION: GUIDELINES AND STRATEGIES FOR DIAGNOSING, MANAGING AND TREATING DEPRESSION
ELLEN FELDMAN, MD
Dr. Feldman is a child and adolescent psychiatrist with 30 years in healthcare and 8 years in medical writing. She has worked in the Department of Behavioral Health, Altru Health System, Grand Forks, North Dakota, since 1998. Dr. Feldman has chaired the Department of Behavioral Health since 2010. Dr. Feldman is skilled in providing holistic, team-based care in various settings.
This course reviews current guidelines and evidence-based practices for the diagnosis, treatment, and management of depression in clinical settings. Beginning with a brief historical perspective on depression, the course delves into epidemiologic data to highlight the widespread impact of this often debilitating disorder. The review outlines diagnostic criteria, common presentations, risk factors, and co-morbidities and thoroughly examines pharmacologic and non-pharmacologic evidence-based treatments. Clinical vignettes are incorporated throughout the paper. An emphasis on multi- disciplinary team involvement illustrates the vital role of interprofessional collaboration in achieving optimal patient outcomes.
RxCe.com LLC is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education.
Universal Activity Number (UAN): The ACPE Universal Activity Number assigned to this activity is
Pharmacy Technician 0669-0000-23-171-H01-T
Credits: 2 hours of continuing education credit
Type of Activity: Knowledge
Media: Internet/Home study Fee Information: $6.99
Estimated time to complete activity: 2 hours, including Course Test and course evaluation
Release Date: October 16, 2023 Expiration Date: October 16, 2026
Target Audience: This educational activity is for pharmacists.
How to Earn Credit: From October 16, 2023, through October 16, 2026, participants must:
Read the “learning objectives” and “author and planning team disclosures;”
Study the section entitled “educational activity;” and
Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)
Credit for this course will be uploaded to CPE Monitor®.
Learning Objectives: Upon completion of this educational activity, participants should be able to:
Define and differentiate Major Depressive Disorder according to DSM V-TR and ICD criteria
Recognize the signs and symptoms of depression
Address the role of counseling and patient education
Understand the role of screening tools in the diagnosis and management of depression
Review evidence-based pharmacologic and non-pharmacologic treatment strategies for depression
The following individuals were involved in developing this activity: Ellen Feldman, MD, and Pamela Sardo, PharmD, BS. Pamela Sardo was an employee of Rhythm Pharmaceuticals until March 2022 and has no conflicts of interest or relationships regarding the subject matter discussed. There are no financial relationships relevant to this activity to report or disclose by any of the individuals involved in the development of this activity.
© RxCe.com LLC 2023: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.
Depression, a prevalent and disabling condition, emerges from a complex interplay of biological, environmental, and psychosocial factors. Its multifaceted nature poses challenges in its identification, treatment, and ongoing management. Unlike many other medical conditions, depression lacks definitive diagnostic tools such as imaging studies, blood tests, or pathognomonic markers. This course reviews current guidelines and evidence- based practices for the diagnosis, treatment, and management of depression in clinical settings.
The Clinical Presentation of Depression
The clinical presentation of depression can vary greatly due to age, gender, cultural background, and personality traits, further complicating accurate and timely diagnosis. Paradoxically, the pervasive feelings of hopelessness and despair associated with depression often impede patients’ adherence to treatment regimens.1,2
The management of depression poses challenges, in part due to its chronic and recurring nature. Frequently occurring comorbid conditions, including other mental health disorders, substance abuse, and physical disorders, complicate the disease course. Stigma, shortage of mental health support, and lack of community resources are also major obstacles in efforts to combat depression. Patients may present with somatic – bodily symptoms (such as headaches or stomach pain) – and be reluctant to discuss underlying feelings related to depression, such as worthlessness, hopelessness, and suicidal thoughts. However, recent studies have shown that applying principles developed for the management of chronic diseases (such as diabetes, obesity, or hypertension) to depression has the potential to facilitate the evaluation and adjustment of treatment over time.1-3
Over half of the eight million depression-related provider visits yearly in the US occur in a primary care setting, highlighting the significant role of frontline medical providers in detecting and managing this disorder.3 The goal
of this course is to provide members of the frontline healthcare team with up- to-date guidelines regarding depression diagnosis, treatment, and management.
The term “depression” refers to major depressive disorder (MDD) as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR),4 and/or International Statistical Classification of Diseases and Related Health Problems (ICD-11).5
While these diagnostic tools both contain symptom lists, it is crucial to understand that the treatment of depression goes beyond merely checking off symptoms. Treatment decisions depend on thoroughly evaluating the degree of functional impairment caused by symptoms to minimize their impact. Thus, accurate diagnosis, effective treatment, and long-term management of depression often rely on a comprehensive patient history, a complete physical examination, and fostering a stable and ongoing patient-provider relationship.1-5
This course begins with a concise discussion of the historical context of depression in the Western world. Subsequently, it delves into the epidemiology of depression in modern times, providing an overview of its prevalence and impact. Finally, the course focuses on exploring diagnostic criteria, risk factors, common comorbidities, and evidence-based treatments associated with depression.
Depression may seem to be a disorder arising from the complexities and stressors of modern-day life. However, the collection of symptoms we recognize as depression today has been understood to represent a medical condition for centuries, transcending temporal and cultural boundaries. Individuals with symptoms of depression are depicted on scrolls and tablets from ancient Egypt.6 Later, in the 5th century B.C., Hippocrates described a syndrome termed ‘melancholia’ as “aversion to food, despondency,
sleeplessness, irritability, restlessness” – symptoms of depression still valid today.7
While Hippocrates advised treatments such as bloodletting, he recognized the value of diet and exercise in treating this condition. During the Middle Ages, religious ideation regarding depression and other mental illnesses became more prominent, giving rise to early mental asylums to isolate those “possessed” by demons and offering exorcism as a treatment.7,8
The 1600s and the Renaissance gave rise to a growing understanding that the etiology of depression may be found in the brain or arise from a combination of environmental stressors and brain abnormalities. This realization helped fuel a shift in treatment approaches towards methods like music therapy, exercise, and social interventions.7-9
Research on the causes of depression persisted well into the 18th and 19th centuries. Debate arose over whether depression stemmed more from biological issues, environment, or unchangeable character traits. Various treatments, including near-drowning experiences, spinning stools, and electric shocks, were studied. Long-term Institutions became popular due to the misbelief that depression stemmed from inherent character flaws.7-9
By the early 1900s, Freud’s theories and psychoanalysis became the main treatment. When this approach fell short (especially for those with severe depression), some turned to lobotomies.7-9
A significant breakthrough came in the 1950s when the antidepressant properties of monoamine oxidase inhibitors were discovered. Following this, another type of antidepressant known as tricyclic antidepressants was developed. These discoveries strengthened the theory that depression was tied to a chemical imbalance in the brain. While these medications showed promise in treatment, serious side effects made them less suitable for many patients.10
A turning point arrived in 1987 with the production of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline. These newer antidepressants (with more tolerable side effects) spurred a surge in prescriptions.10
Entering the 21st century, our understanding of depression is becoming more nuanced. We now have evidence of a multifaceted etiology of depression involving a complex intermixing of biological, psychological, and social factors. This understanding has led to a diverse range of treatment options such as antidepressants, talk and behavioral therapies, lifestyle change, and even newer treatments such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMR).10,11
Despite advances in our knowledge, the stigma surrounding depression has not entirely faded, and many people worldwide do not receive timely and accurate diagnosis, treatment, and care for this disorder.1,2
Depression is not a 21st-century phenomenon, and the stigma of the past may still impact views of depression today.
A few statistics can enlighten clinicians on the breadth and impact of depression. Recognized by the World Health Organization (WHO) as the top cause of disability worldwide, depression affects a staggering 5% of the adult world population and 5.7% of those over age 60. This prevalence implies a high likelihood that depression has impacted a colleague, friend, or family member. Furthermore, it is probable that patients, clients, and customers who interact with healthcare professionals daily have been touched by depression.12
Depression is associated with elevated mortality rates as well. Fatalities from cardiovascular disease are significantly worsened when depression is present, and depression is a major risk factor for suicide. Alarmingly, suicide is the fourth leading cause of death worldwide among 15 – 29-year-olds.12,13
Prevalence rates for depression vary with gender and specific medical and psychological situations. For example, depression occurs about 1.5-2 times more in women than men, adverse psycho-social circumstances such as poverty and trauma impact the expression of depression, and comorbidity between depression and other chronic conditions complicate the disease course.12-14
Genetics contribute to an estimated 37% of depression cases, a proportion considerably smaller than for other disorders of mental health. This underscores the powerful impact of environmental and other stressors on depression emergence and course.13,14
Despite our advanced healthcare system, studies show the USA is not immune from these patterns. Individuals with depression miss work close to twice as much as persons without this disorder. Higher medical costs and disruption to occupational and personal lives all contribute to the high economic burden of depression.15
The 2020 National Survey on Drug Use and Health revealed more facts about the state of depression in the US.15 According to this comprehensive study, 21 million adults, or 8.4% of all US adults, reported experiencing an MDD.15 As expected, the prevalence was higher in women than men, with rates of 10.5% and 6.2% respectively. Younger adults, as opposed to those over 65, displayed the highest rates of depression.15 Regarding racial demographics, individuals identifying as multi-racial reported the highest prevalence of depression at 15.9%.15
The National Institute of Mental Health reported on the percentage of adult and adolescent patients who received treatment for MDD during 2021.15 About 61% of US adults (≥18 years of age) diagnosed with MDD episodes
received treatment, which rose to 75% when studying treatment for adult patients with severe impairment from MDD.15 The percentage of US adolescents treated for MDD episodes was about 41%, with treatment for severe impairment being only about 3 points higher (44.2%).15
Notably, depression does not always “fly solo.” Often emerging from or leading to other chronic conditions, depression can be viewed as a part of a challenging cycle of comorbidity that amplifies morbidity risks. For example, depression is commonly seen in conditions such as cardiovascular disease, diabetes, end-stage renal disease, neurologic disorders, other disorders of mental health (especially anxiety disorders), and substance abuse disorders. Sometimes, depression itself can be a risk factor for the development of the comorbid condition. In all cases, recognizing the comorbidity is critical for effective treatment.16
Prevention is key to managing depression. About 40%-60% of those who recover from a depressive episode experience recurrence, with increasing risk after each episode.16 All members of the frontline healthcare team play a critical role in identifying and supporting those impacted; effective and timely treatment for depression often can interrupt or mitigate this cycle.17
Take-home message: Depression is common, treatment is not always available, and the disorder may become chronic and complicated.
Symptoms of depression are meticulously delineated in the DSM-5-TR and ICD-11.4,5 A working knowledge of these documents is essential in recognizing this complex disorder. While it may be possible to use either of these as a stand-alone reference to diagnose, their optimal use is to guide an in-depth clinical interview.4,5
Despite a significant overlap between these two systems, there are key differences. In the USA, most providers apply DSM’s diagnostic criteria but turn to ICD codes for billing purposes. Thus, a basic familiarity with each system is useful. To compare the diagnostic criteria, refer to Tables One and Two – these outline the specifics of diagnosing depression based on each system.
A major depressive disorder meets the following criteria:
Five or more symptoms listed in the chart below have been present for at least two weeks. Symptoms must include either depressed mood and/or loss of interest and/or loss of energy.
Symptoms result in a deterioration in functioning.
Symptoms are not better explained by another psychiatric disorder, are not due to effects of a substance or pharmaceutical agent and are not due to another medical condition.
There has never been a hypomanic or manic episode, and current symptoms do not meet the criteria for a mixed episode; if any of these are present, look towards bipolar disorders.
Table 1: Major Depressive Disorder DSM-5–TR4
|List of Symptoms
|Depressed mood most of the time
|By self-report or observation
|Markedly diminished interest or pleasure
|Significant change in weight or appetite
|Without deliberate efforts at dieting
|Insomnia or hypersomnia
|Psychomotor agitation or retardation (“slowed down”)
|Observable by others
|Feelings of worthlessness or guilt
|Excessive or inappropriate
|Decreased ability to think or concentrate
|By self-report or observation
|Recurrent thoughts of death – not just fear of death
|May include suicidal ideation, may include plan for suicide
Depressed mood or decreased interest in activities must be present for at least two weeks. Other accompanying symptoms may include the symptoms listed in Table Two. No history of manic, hypomanic, or mixed episodes is present in this case.
Table 2: Criteria for ICD-11 Depressive Disorder5
|In multiple settings
|Profound feelings or worthlessness or guilt
|Inappropriate or excessive to situation
|Hopelessness with recurrent thoughts of death
|May include suicidal ideation or plan
|Changes in sleep patterns and/or appetite
|Reduced energy and motivation
Notably, the DSM5-TR and ICD11 diagnostic criteria overlap in multiple areas. Both systems emphasize the necessity of at least one key symptom: depressed mood or loss of interest or energy. The persistence of these symptoms for at least two weeks and in sufficient severity to interfere with daily functioning is a mandatory criterion for both systems. The DSM5-TR
additionally stipulates the presence of at least five out of nine additional symptoms, whereas ICD-11 acknowledges other accompanying symptoms without specifying a count. It is important to note that a person diagnosed with depression using DSM-5–TR criteria will likely fit the ICD-11 criteria but the reverse is not always true.4,5
Both systems categorize depressive episodes as mild, moderate, or severe based on the number, type, and severity of symptoms, with a key focus on the level of functional impairment. For example, patients with mild depression may experience five – six symptoms but have a minimal change in functioning, while a patient with severe depression will typically describe more symptoms and will experience more significant interference with daily functioning. This is where patient history becomes vital, and sometimes, multiple visits may be required to fully understand the degree of impairment.4,5,18
To illustrate how depression may be assessed and treated, a hypothetical Case Example of LM, a 42-year-old lawyer, multi-racial female, will be used and referred to throughout this course. LM reported that she is having trouble concentrating. She is not taking regular medication. LM came in for an appointment to see if she “needs something for concentration.” She stated, “I wonder if I have adult attention deficit disorder.” She reported that her ability to focus and concentrate has changed over the last 6-8 months. She reported progressive difficulty completing work, finds herself losing track of details, and says, “I feel like I am letting everyone down.” As a result, she said she stays late at work but still is not productive. She has noticed increased tearfulness both at work and home, has difficulty getting to sleep (“I just keep thinking how I am failing everyone”), a 5-7 pound weight gain (“no time for the gym anymore”), and a profound decrease in motivation saying, “everything feels like it is so much effort.” She stated her husband thinks she is less interested in interacting with him and their two children, ages 2 and 6, but “if I could perform at work the way I used to, I think everything else would change as well.”
Recognizing depression in a primary care setting is a complex task. Often, patients present with non-specific symptoms such as decreased energy, general body aches, or digestive concerns rather than expressing concerns about their mood. Somatic complaints (including insomnia, headaches, poor concentration, or pain) are likely reasons for a visit. Interestingly, it is usually towards the end of the visit, if at all, that concerns about depressed mood arise. Depression screening tools, self-administered during routine visits, have been adopted to improve the recognition of depression in these settings.18,19
The US Preventive Service Task Force (USPSTF) is among several national medical groups recommending screening for depression in all adults, including pregnant and postpartum women during primary care physician (PCP) visits. Furthermore, the USPSTF recommends that there be “adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up.”18 This statement reflects the understanding that a diagnosis of depression may begin with screening but that screening alone cannot adequately diagnose or manage this condition.18,19
The Patient Health Questionnaire (PHQ), available in two and nine-item versions (PHQ-2 and PHQ-9), is the screening instrument of choice for most clinicians. The PHQ is distributed without charge, is easy to use in an office or similar setting, and is self-completed within a few minutes. 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 5-27 representing mild to severe depression on the PHQ-9 and a score of 3 (out of 6) representing depression on the PHQ-2. The diagnostic specificity and sensitivity of these two scales vary, with the PHQ-9 having a more established record of reliability. It is important to keep in mind that these tools and others like them must be used in tandem with a comprehensive history and physical – a screening tool alone cannot suffice for a depression diagnosis.20,21
Returning to the hypothetical Case Example, LM fills out the PHQ2 and checks off “more than half the days” regarding question one (“Little interest or pleasure in doing things”) and “some days” in response to question 2
(“Feeling down, depressed or helpless”), totaling to a score of “3” - the threshold for depression on this screen. When you ask her about these responses, she says, “It just is hard feeling torn between my family and work… sometimes it feels like there is no way to please everyone, and as a result, I please no one.”
The results of the screen serve as a bridge into a discussion on depression and associated risk factors during the clinical interview. Expressing empathy (for example, “It must be tough feel that way.”) can foster trust and build a stronger clinical alliance.18,22
Risk factors significantly influence a diagnostic evaluation for depression. The most potent risk factor is a previous depressive episode; individuals with this history are at higher risk for future episodes. This underscores the cyclical nature of this disorder. Other substantial risk factors include past mental illnesses, substance misuse, a family history of depression or suicide, chronic medical conditions, recent stressful life events, unemployment, and experiences of domestic abuse. All of these factors can shape the direction of the diagnostic interview and heighten the risk of depression.18,22
Take-home message: Understand the diagnostic criteria for depression, adopt the use of at least one screening tool, be ready to follow up screens with targeted interviews, and review risk factors.
Differential Diagnosis and Comorbidity
In some cases, patients may exhibit signs of depression that do not match the full criteria for MDD. Here, consulting the DSM5-TR becomes an invaluable tool in discerning whether these patients align more closely with other depressive disorders such as Disruptive Mood Dysregulation Disorder, Premenstrual Dysphoric Disorder, Unspecified Depressive Disorder, and the more subtle yet enduring Persistent Depressive Disorder.4
Comorbid Disorders of Mental Health
It is also crucial to consider that other psychiatric conditions, notably anxiety and substance use disorders (SUD), frequently co-occur with depression. Surprisingly, more than half of depressed patients may struggle with co-existing anxiety, a combination that often makes remission more challenging. Therefore, routine screening for anxiety, especially in patients with poor treatment response, is recommended to help unearth an underlying anxiety disorder. Utilizing a tool like the Generalized Anxiety Disorder Scale (GAD 2 or GAD 7) is useful. Keep in mind, a negative anxiety screen has a higher predictive value than a positive and as with all screens, these tools are most valuable when paired with a diagnostic interview.23,24
Depression and SUD comorbidity rates fluctuate between 8.6% and 25%. In a survey of 2,500 outpatients suffering from depression, younger males with an early onset of depressive symptoms and high functional impairment faced a notably heightened risk of SUD. Incorporating non- judgmental substance-use inquiries into routine assessments with depressed patients can often lead to a more precise diagnosis, which facilitates treatment plans targeted at both disorders.18,25
Equally important to remember is that patients with bipolar disorder often enter the clinical setting with depression or low mood. To prevent misdiagnosis and the potential harm of prescribing unsuitable antidepressants, the DSM and ICD guidelines urge providers to stay vigilant for signs of mania or hypomania predating the depressive episode. Asking about periods of unusual elevation of mood, irritability, and/or poor sleep partnered with excessive energy could reveal suggestive of mania, guiding treatment away from potentially harmful antidepressants and towards mood stabilizers.18,26
Medical Conditions and Medications
Lastly, be aware of the symptom overlap between certain medical conditions and depression. Several common disorders, such as thyroid disease and anemia, can mimic the poor energy and fatigue often seen in depression. Likewise, neurologic conditions like Parkinson’s, multiple sclerosis, and dementia can present with low mood and cognitive changes that bear a striking resemblance to depression. Thorough history taking, physical examination, and diagnostic lab testing can be pivotal in distinguishing these conditions.18,22
For those with recent changes in medications, a detailed evaluation of the timeline of symptom emergence and functional changes is especially pertinent. Many drugs, including beta-blockers, some oral contraceptives, and steroids, can provoke depressive symptoms. Many patients will not connect changes in non-psychotropic medication with mood problems; it is useful for the PCP and pharmacy team to be proactive in letting a patient know to be vigilant for such side effects.18,22
Case Example: LM notes she was mildly “down” after the birth of her second child two years ago, saying, “I just felt like I couldn’t give her my all because our older child needed me too.” She doesn't think she is depressed now (“just stressed”) but notes her family history is strong for both depression and anxiety.” When asked about substance use, she denies using marijuana, tobacco products, or illicit drugs. When asked what has helped her sleep, she pauses and says, “the only thing that helps is wine – and I notice that my one glass before bed has become two to three glasses and sometimes more on harder nights.” Her physical exam is unremarkable except for the weight gain and mild elevation of pulse. She denies suicidal thinking or intention, but says, “there are many days I fall asleep wishing I would not wake up in the morning – life really feels too hard.”
Take-home message: Carefully evaluate symptoms and look for other mental health disorders, comorbid substance abuse, and other medical conditions and medications.
Evaluating Suicidal Risk
Depression heightens the risk of suicide, suicide attempts, and self- harm, a serious aspect of mental health that should not be underestimated.27 A 2019 review of literature from 2000 to 2017 demonstrated that nearly half of adults who completed suicide had seen a PCP in the month leading up to their death, with 80% having contact in the year before suicide.28 Considering that many suicide attempts involve medications, it is understandable that pharmacists, as well as the PCP, will frequently encounter patients at risk for suicide. A 2019 study found that 22% of 500 community pharmacists surveyed knew a patient who had committed suicide, and 21.6% had received a request for a lethal dose of medication.29 Alarmingly, many clinicians feel unprepared to evaluate or respond to these high-risk patients.27-29
Even though patients may be reluctant to express thoughts about suicide directly, they tend to be more responsive to open-ended questions. Routinely asking patients with depression or depressive symptoms about suicidal thoughts, plans, or intentions can initiate a discussion. While tools such as the Columbia Suicide Severity Rating Scale (C- SSRS) offer beneficial insights, these screens cannot replace a careful diagnostic evaluation or stand alone in representing suicidal thinking.30
Consider prompt referral for patients with high-risk factors and suicide intention to specialists. The availability of mental health providers can vary by region, which invariably influences referral and consultation patterns.31,32
There is increasing evidence that collaborative care models – involving a team including the PCP, pharmacist, and other front-line professionals as well as mental health specialists – can lead to more effective care for higher- risk patients with depression. For example, a pharmacist team member often
has contact with a patient between structured office visits and thus may be well positioned to alert the patient to report mood or functional changes to the health care team.32-34
Telemedicine, too, is showing promising efficacy and offers an opportunity to bring specialty care to communities previously lacking these services.35
Whatever the delivery method, it is important to have robust working relationships between primary care, community pharmacists, and local mental health providers.32-34 Providing patients with information about supportive resources, including support groups and services such as suicide hotlines, can create an additional safety net for these individuals.30.31
Take-home message: Know how to evaluate for risk of suicide and where to refer.
Depression is a recurrent, chronic disorder. As such, management of depression in primary care follows the model of management of other chronic conditions. Monitoring symptoms, function, side effects (from any prescribed medications), and treatment adherence is ideally accomplished by establishing a team with representation from multiple disciplines, including primary care, behavioral health, pharmacy, and nursing working with the patient.32-34
Treatment outcomes can be conceptualized as three interrelated stages: response, remission, and recovery.36 ‘Response’ is when symptoms drop by 50% from the start point. ‘Remission’ is the return to normal functioning with minimal symptoms. The ultimate goal is ‘Recovery’ – a state of remission lasting longer than two months.33
Unfortunately, depression may also relapse (resurface before reaching recovery) or recur (emerge as a new episode.)33,36 About 10-15% of primary care patients with depression never fully recover, especially those showing higher dysfunction at the start. The recurrence rate stands at over 40% after the first episode of depression, highlighting the importance of long-term prevention.16
A recent study from the Netherlands looking at a relationship between waiting time and initiation of treatment for depression in primary care found evidence of an association between longer waiting times and poorer outcomes. This again speaks to the importance of prompt identification and treatment in depressed patients.34
Evidence-based guidelines for the treatment of depression in primary care suggest targeting the initial approach according to the severity of the presentation.24 Psychotherapy and lifestyle modifications are recommended for mild cases, while pharmacotherapy is generally recommended for more severe cases or when initial symptoms do not respond adequately. One rationale for these differences in treatment is that the effectiveness of antidepressants varies based on the severity of symptoms, with smaller effects observed in cases of mild depression. It is important to note that the severity of functional impairment is the most important factor when determining the severity of the overall condition and appropriate treatment intensity.37
Cognitive behavioral therapy (CBT) is a structured talk therapy that has consistently shown effectiveness in treating depression.38 It may be delivered individually or in a group. While other therapies like problem-solving or interpersonal therapies may have equal or greater impact, more research and head-to-head investigations are needed to draw firm conclusions. Home or office-based treatments, including guided self-help and computerized CBT, have limited efficacy, and further high-quality studies are required to determine their potential role in depression treatment. Additionally, there is
suggestive evidence that generic “psychological counseling” can have an impact similar to CBT.34
Mindfulness-based cognitive therapy (MBCT), an eight-week program combining CBT techniques with mindfulness practice, has been specifically studied for the prevention of depression.39 Although research on its efficacy and mechanism of action is ongoing, the American Psychologic Association endorses MBCT as a viable treatment to prevent depression relapse. Many guidelines for depression prevention amongst high-risk patients worldwide also incorporate this therapy. However, the limited availability of groups may hinder access to MBCT, prompting ongoing studies on self-help MBCT and virtual dissemination.39
Investigations exploring factors influencing therapy success have highlighted the significance of the patient-therapist relationship and patient expectations, which may have a greater impact than the type of therapy used.34 Interestingly, patient expectations of response to medication also play a role in predicting treatment outcomes when pharmaceutical intervention is utilized for depression. This holds relevance for the PCP when making decisions about treatment direction and intervention, as well as when evaluating treatment response. Involving patients in decisions regarding therapy referral and/or medication provides an opportunity to understand the patient's perspective and address any concerns they may have about specific forms of treatment.34
Case Example: LM repeated that she is not convinced she has depression. She does not want to see a therapist, saying, “It probably would help, but I don’t have time!” She admitted she is worried about her escalating use of alcohol to obtain sleep and notes her husband also expressed concern. She expressed surprise that the insomnia, poor concentration, lack of energy, and emotional distancing she described could all result from depression. “If I go on medication, I don’t want to be on medication forever,” she said, “that’s what happened with my mom.”
Medications for Treating Depression
Medications for treating depression include SSRIs, SNRIs, NDRIs, and TCAs.16,40-42 These acronyms may sound like alphabet soup, but they represent a range of FDA-approved antidepressants with specific neurochemical targets. With more than 30 options available, it is easy to get lost in the sea of choices. However, understanding the basics can help navigate this complex landscape.16,40-42
Traditional antidepressants aim to increase the availability of serotonin, norepinephrine, and/or dopamine in the brain.16,40-42 In recent years, new antidepressants with novel mechanisms of action have emerged. In 2023, the FDA approved three such agents: esketamine (a nasal spray derived from ketamine), brexanalone (administered intravenously for post-partum depression), and dextromethorphan-bupropion (a dual-action and fast-acting option.) These newer agents are typically prescribed by specialists as there is limited (but growing) evidence supporting their use as first-line treatment. This course will primarily focus on the more established medications.42
When choosing an antidepressant with a patient, it is crucial to consider various factors. First and foremost, obtain input from the patient in order to understand their target symptoms (such as sleep disturbance, cognitive dulling, or appetite changes, for example) The functional impairment from specific symptoms should guide the decision-making process. Additionally, assess the patient’s expected tolerance for side effects, review the personal and family history of psychotropic medication use, evaluate the potential for interaction with other medications, and consider affordability or insurance restrictions.16,40-42
Patients should be counseled that the response to most antidepressants takes a few weeks.34 Recommendations from large-scale studies are to use a stepped approach, with frequent re-evaluation and sequential treatment adjustment. A typical scenario is to evaluate the tolerance for the antidepressant at weeks one to two and look for a response by weeks three to four. If there is no response at all, consider an increase in dose or change
to a different agent. Remember that some individuals are slow responders, so be prepared to wait longer for a full response if there is any suggestion of impact during the initial period.34
Specialist consultation is warranted if two antidepressants are tried (from the same or different categories) singularly or in combination at adequate doses and duration without a response. Mental health providers may look at adding in an atypical antipsychotic such as aripiprazole or quetiapine, re-evaluate for a different or overlapping psychiatric disorder, and/or consider a treatment such as electroshock or related therapy.43
Before referral, it may be helpful to evaluate medication adherence. Non-adherence with antidepressant treatment has been observed in multiple studies, making it advisable to work collaboratively with the patient and pharmacist to ensure medication compliance and assess the use of other pharmaceuticals that may influence mood. Additionally, throughout each step, consider and address lifestyle factors that could impede progress.34,44,45
Tricyclic Antidepressants (TCAs); e.g., Imipramine
These first-generation antidepressants are not as commonly used for depression due to adverse cardiovascular side effects, significant anticholinergic effects, and the potential for lethality in overdose.46 However, TCAs like nortriptyline still have a role in treating insomnia associated with depression, thanks to their significant sedating properties.46
Selective Serotonin Reuptake Inhibitors (SSRIs), e.g., Fluoxetine
Selective Serotonin Reuptake Inhibitors are the most commonly prescribed antidepressants in the USA and globally, although the popularity of specific types may vary regionally. These agents are generally well tolerated, with common side effects including gastrointestinal disturbance and headache. However, it is worth noting that they can also cause sexual dysfunction and weight gain. Moreover, all of these agents increase the risk
of abnormal clotting and bleeding, especially when combined with non- steroidal (NSAIDs) and anticoagulants.16,34,44
Close relatives of SSRIs, with similar side-effects and efficacy profiles, include the following:
Serotonin-norepinephrine reuptake inhibitors (SNRI) such as duloxetine, venlafaxine, and desvenlafaxine16,34,44
Serotonin antagonists and reuptake inhibitors (SARI) such as trazodone, an older antidepressant with sedating properties even at low dose.16,34,44
Atypical and Newer Agents
Bupropion, classified as a norepinephrine and dopamine reuptake inhibitor (NDRI), and mirtazapine, a noradrenergic specific serotonin antidepressant (NaSSA), fall under the category of atypical antidepressants.45 In addition, there are newer agents such as vilazodone, a serotonin partial agonist reuptake inhibitor (SPARI), vortioxetine, which acts as an SSRI and receptor modulator; and levomilnacipran, an SNRI.45
Clinical Pearls Regarding Antidepressants Boxed Warning
The FDA issued a “boxed warning” in 2005 regarding the increased risk of suicidal thoughts in children, adolescents, and young adults taking an anti- depressant, particularly early in treatment.47 While there is debate surrounding the validity of the findings and the usefulness of the warning, clinicians should discuss the warning with patients, carefully weigh the risks of medication treatment, and closely monitor their patients.16,34,44,47
Stopping an Antidepressant
Recent studies suggest that the increase in the use of antidepressants worldwide is in large part attributable to long-term antidepressant use.
However, research notes an antidepressant course from six to twelve months following remission of the first episode of depression, depending on risk factors, can decrease the risk of relapse by 65%.48
When discontinuing an antidepressant, it is recommended to taper the dose slowly after a successful treatment course while closely monitoring for ant resurfacing symptoms. However, for individuals with a history of three or more episodes of depression, maintenance medication may be necessary to achieve remission.48
Abrupt discontinuation of most antidepressants can lead to a condition called discontinuation syndrome. Symptoms such as irritability, dizziness, electric shock sensations, and tearfulness may emerge within days of stopping the medication. These symptoms can either resolve on their own or become more pronounced, interfering with functioning. Medications with shorter half- lives, like paroxetine and venlafaxine, have a higher risk of discontinuation syndrome. To mitigate this phenomenon, a gradual tapering of doses over four to six weeks is recommended.16,34,44
Serotonin syndrome, a potentially life-threatening condition, may occur due to serotonergic drug overdose or unforeseen interactions. It can range from mild symptoms such as agitation and confusion to severe manifestations, including seizures and coma. Prompt recognition and appropriate management are essential to prevent complications.16,34,44
Cytochrome P450 (CYP450)
Most antidepressants interact with the CYP450 system, potentially resulting in clinically significant drug interactions. Antidepressants with the strongest inhibitory impact on the CYP450 enzymes are fluoxetine (Prozac), fluvoxetine (Luvox), paroxetine (Paxil), and bupropion (Wellbutrin). It is important to be aware of the potential for interactions with other medications and to consider dosage adjustments.49
Case Example: LM reported she is willing to hear information about medication and was relieved to learn that other nonpharmaceutical interventions may help and that she can have medication for a limited and defined time. Of the antidepressants, she said she was concerned about potential sexual side effects with any SSRI but interested in bupropion because of less likelihood of such a side effect. The provider was concerned about the activation potential of bupropion interfering with sleep but recognized that the dopaminergic activation may help with energy and focus. LM agreed to stop the evening wine and thinks she could discuss getting back to routine exercise with her husband – “He has been bugging me to go to the gym like we used to,” she noted. LM agreed to try bupropion at 150 mg xl in the am, along with restarting exercise, stopping the evening alcohol, and changing some of her work habits would be a good start. Follow-up was arranged with the provider and she is willing to call the office health coach within a week to check in.
Take-home message: Mild depression may be treated with lifestyle changes and specific psychotherapies; more severe depression may warrant the use of psychotropic medication and other interventions.
Adjunct Interventions in the Treatment of Depression
Studies show promise in utilizing interventions to decrease social isolation, improve sleep quality, promote physical activity, and implement nutritional changes for the treatment of depression. However, the effect size of these interventions is generally modest. Further research is needed to identify specific populations where dietary intervention may be most successful. A large meta-analysis of 49 prospective studies found that physical activity is associated with a reduced likelihood of developing depression but has less of an impact on symptom reduction, depression severity, or the course of an acute depressive episode.35,50,51
The importance of sleep on mood is well-established, but further research is needed to determine if sleep improvement alone can effectively mitigate depression.52
Limited and low-quality studies exist regarding the impact of addressing social isolation to alleviate depression.53 A large-scale cohort study from the UK found a significant correlation between low levels of social support and depression during the COVID-19 pandemic, alongside pre-existing physical and mental health conditions, experience of misuse, and lower socioeconomic status.53
None of these adjunct measures has shown effect sizes comparable to conventional medication or psychotherapy. However, incorporating these health and lifestyle measures as part of an overall treatment plan can potentially enhance the response to the treatment of depression.34,43,48-51
Consider recommending these measures as first-line options for patients with mild depression, particularly when they are not interested in psychotherapy or psychotropic medication and when risk factors are minimal. Working collaboratively with the patient over a defined period to improve diet, increase physical activity, enhance sleep, and foster socialization allows for a comprehensive evaluation of symptoms and functioning over time.34,43,48-51
A pharmacist can be a key person in a patient suffering from social isolation, poor sleep quality, low physical activity, and who needs to make dietary changes. The pharmacist may advise the patient to contact his or her primary healthcare provider to address these concerns.
The pharmacist and pharmacy team could also keep on hand resources to give to patients if they do not have a primary care provider, such as the Friendship line 800-971-0016, which provides emotional support for those over age 60, https://www.ioaging.org/services/friendship-line/, or the Youth Crisis Hotline 800-852-8336. https://www.teenline.org/youth The SAMHSA hotline is also a good resource. 800-662-4357. https://www.samhsa.gov/. There is a national Dial 988 for crisis line, Chat at
988lifeline.org (free 24/7 support), a national sexual assault hotline 800-656- 4673, and NAMI Help Line 800-950-6264 https://nami.org/help.
Take-home message: Consider lifestyle changes in collaboration with the patient – consider social interaction, sleep improvement, nutritional intervention, and physical activity.
Older Adults and Medical Comorbidities
Older adults and individuals with medical comorbidities require caution when initiating pharmacotherapy for depression. Starting with a low dose and careful monitoring is essential. Observational studies in older adults indicate an increased risk of falls and fractures with SSRIs and SNRIs. Note that SSRIs can elevate the risk of gastrointestinal bleeds and potentially cerebrovascular bleeds.54
Cardiovascular disease and depression often co-exist and influence each other. Recent investigations focusing on heart rate variability and inflammatory status aim to elucidate the mechanisms linking these disorders. Antidepressant treatment appears to be particularly beneficial for patients with this particular combined condition.55
While antidepressant-induced hepatotoxicity is rare, it is a possibility. A French cohort study involving five million participants identified 382 cases of serious liver injuries associated with antidepressants, with no significant difference among the type or class of antidepressant prescribed. However, duloxetine, bupropion, and trazodone are known to have a slightly higher likelihood of causing drug-induced liver injury. For patients with polypharmacy or at risk for liver disease, obtain baseline liver function tests. In patients with known liver disease and depression, using an SSRI at a low dose is preferable.56
In older adults and patients with medical comorbidities, polypharmacy increases the risk of side effects and may necessitate dosage adjustments for antidepressants. Non-pharmacologic evidence-based treatment for depression may be beneficial in many of these cases.55
Case Example Conclusion
LM came in for her first follow-up visit at two weeks. She noted that she and her husband decided to change the family evening routine, removed alcohol from the house for now, and divided household responsibilities in a different manner. She noted that she was feeling more effective at work and coming home earlier with more energy. She had no significant side effects from the bupropion and was just starting to fall asleep easier – which she thinks may be due to exercising with the family in the early evening.
At week six, LM’s score on the PHQ2 had dropped to a “2” as she checked off that he had “little pleasure in doing things” and times of “feeling down” only a few days over the last two weeks. She noted she remains on 150Xl of bupropion but wonders if she should continue, stating, “I think what actually helped me the most is that I stopped isolating and drinking at night, and I decided to come home from the office on time – no matter what.” After a short discussion about her responses on the PHQ2, antidepressant treatment, and the natural course of depression, she agreed it makes sense to continue at least a six-month course and to check back within another month.
LM’s course effectively illustrates the multi-faceted nature of depression and emphasizes the significance of consistent follow-up. The patient’s central role in identifying and prioritizing target symptoms in the treatment of depression is highlighted. Given that helplessness is a common symptom of depression, empowering patients to actively participate in their treatment can serve as a powerful therapeutic intervention and enhance compliance, making the patient feel a valued part of the treatment team.
Access to mental health expertise is limited throughout the USA, often making the PCP the first line of defense for patients with depression.
It is recommended to screen adults in primary care for depression at least once. If screens suggest depression, follow up with a diagnostic interview and comprehensive physical.
Establish a system to evaluate risk factors and initiate evidence-based treatment that considers the patient’s preferences regarding intervention type and target symptoms.
Collaborate and connect with local mental health providers and organizations for referral and coordinated care.
Adopt a holistic approach to this chronic disorder, which involves periodic follow-up and active monitoring, particularly for patients with high-risk factors or comorbid conditions.
Implement evidence-based and adjunct interventions while working with the patient to adjust treatment and improve quality of life, ultimately aiming for remission or recovery from depression over time.
Depression, a prevalent and disabling condition, emerges from a complex interplay of biological, environmental, and psychosocial factors. Its multifaceted nature poses challenges in its identification, treatment, and ongoing management.
Symptoms of depression are meticulously delineated in the DSM-5-TR and ICD-11. A working knowledge of these documents is essential in recognizing this complex disorder. In some cases, patients may exhibit signs of depression that do not match the full criteria for MDD. Here, consulting the DSM5-TR becomes an invaluable tool in discerning whether these patients align more closely with other depressive disorders such as Disruptive Mood Dysregulation Disorder, Premenstrual Dysphoric Disorder, Unspecified Depressive Disorder, and the more subtle yet enduring Persistent Depressive Disorder.
Depression is a recurrent, chronic disorder. As such, management of depression in primary care follows the model of management of other chronic conditions. Monitoring symptoms, function, side effects (from any prescribed medications), and treatment adherence is ideally accomplished by establishing a team with representation from multiple disciplines, including primary care, behavioral health, pharmacy, and nursing working with the patient.
Treatment outcomes can be conceptualized as three interrelated stages: response, remission, and recovery. Response is when symptoms drop by 50% from the start point. Remission is the return to normal functioning with minimal symptoms. The ultimate goal is Recovery– a state of remission lasting longer than two months.
Pharmacy team members are very accessible to patients. They get to know their patients and can recognize the signs and symptoms of individuals who are at risk for depression or who may be experiencing depression. Compassion and listening skills enable an opportunity to refer individuals to a provider for a diagnostic work-up. Pharmacists can educate patients about their conditions and medications. Pharmacy technicians can also be observant when a patient taking antidepressants brings an OTC to the counter. Patients purchasing over-the-counter cold medicines, medications that cause drowsiness, and that contain St. John’s Wort should be referred to the pharmacist for counseling. This helps contribute to successful patient outcomes.
The DSM V-TR and ICD systems both contain symptom lists:
Either can be used to definitively diagnose major depressive disorder (MDD)
Only DSM V TR can be used to definitively diagnose MDD
Either can be used in the process of diagnosing an MDD but must be paired with a comprehensive history and physical examination
Only ICD can be used to definitively diagnose MDD
Comparing DSM V-TR to ICD criteria for major depressive disorder:
DSM criteria are general and nonspecific, which allows broad interpretation of criteria
The severity of symptoms determines the level of depression (mild, moderate, or severe) in both systems
Severity of functional impairment determines the level of depression(mild, moderate, or severe) in both systems
ICD criteria are much more specific than DSM V-TR – if a patient meets the criteria for major depression in ICD, that person will likely meet the criteria under DSM V-TR
Signs and symptoms of depression
always include depressed mood and/or loss of interest and/or energy lasting at least two weeks and leading to functional impairment
always include tearfulness, pessimism, and irritability
are only detectable with specific lab work and/or imaging study
are only detectable by intensive psychological testing
In primary care, depression
must be referred to a specialist for diagnosis and treatment.
can be treated as an acute illness with medication and follow-up as needed.
can be readily diagnosed without the need to rule out other causes for the decline in mood or functioning.
often presents with symptoms of bodily concerns such as headache or stomach pain.
Screen for depression
in order to avoid lengthy interviews with the patient.
in all adults and follow-up positive screens with a diagnostic interview and appropriate interventions.
only in suspected suicidal patients.
only if there is a strong family history of depression.
Management of depression in primary care is best accomplished
with a multidisciplinary team, frequent re-evaluation, gaining an understanding of the patient’s thoughts regarding medication and/or psychotherapy, and education about prevention strategies, as the course of depression is often chronic and recurrent.
by watchful waiting and frequent screening.
with the long-term use of a single antidepressant agent.
by referral to a psychotherapist.
may be treated with long-term antidepressants without psychotherapy and yearly visits as long as the provider is comfortable with this course.
may be treated with psychotherapy (without antidepressant medication), frequent re-evaluation, and symptom monitoring as long as the patient prefers this intervention and responds with functional improvement.
typically resolves after 1 -2 months without treatment.
is not a “real” medical diagnosis.
must always be used by patients with moderate to severe depression, even if the patient is reluctant to take the medication.
have side effects, including a boxed warning regarding the potential of increased suicidal thoughts, especially in children, adolescents, and young adults; this should never be discussed directly with the patient for fear of suggestibility causing suicidal thoughts.
*have side effects, including a boxed warning regarding the potential of increased suicidal thoughts, especially in children, adolescents, and young adults; this should be discussed with the patient along with all side effects, and the patient should be closely monitored.
have a minimal risk of non-adherence.
Risk factors associated with the management of depression in primary care include
pervasive feelings of hopelessness and worthlessness.
insomnia and loss of appetite.
comorbid medical problems, a patient taking multiple medications, concurrent diagnosis of other mental health disorders or substance use disorder, age.
non-adherence with a treatment plan.
When a clinician is assessing or screening a suicidal patient, the clinician should
never ask a patient directly about suicidal thoughts as this could spark suicidal thoughts.
ask routine, open-ended questions regarding suicidal thoughts, plans, or intentions can start a conversation, help with evaluation of the thoughts, and open the door to providing resources.
screens such as the Columbia Suicide Severity rating scale can be used instead of a patient interview.
keep the patient’s disclosure of suicidal thoughts confidential and never share them with other members of the patient care team.
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