Depression Nursing CE Course for RNs and LPNs

ed precision medicine strategies such as biomarker-driven treatment selection and neuromodulation techniques (Harvard Health Publishing, 2021; Jindal et al., 2024; Prompiengchai & Dunlop, 2024).

Risk Factors

              Risk factors for major depression are typically organized into three broad sets: internalizing (emotional) factors, externalizing (behavioral) factors, and adversity factors. Internalizing factors include traits such as neuroticism and anxiety, which predispose individuals to emotional dysregulation and depressive episodes. Externalizing factors encompass behavioral issues such as substance use, impulsiveness, and conduct problems, which can interact with mood symptoms and increase risk. Adversity factors refer to exposure to stressful or traumatic life events, including childhood abuse, loss, social isolation, and chronic medical illness, which can precipitate or exacerbate depressive episodes. Multiple factors contribute to an individual’s risk of developing depression, encompassing genetic, biological, environmental, and psychological influences. Temperament plays a significant role, particularly for those exhibiting negative affectivity—characterized by emotions such as anger, guilt, and nervousness—and neuroticism. Adverse childhood experiences (ACEs), such as abuse, low income, limited education, and discrimination, can predispose individuals to depression, with a pronounced impact on patients assigned female at birth (Gronemann et al., 2025; Jiang et al., 2025; Krishnan, 2025b).

              Genetic factors also elevate the risk; individuals with a first-degree relative diagnosed with depression are 2 to 4 times more likely to develop the disorder themselves. Additionally, having a non-mood disorder, like anxiety or substance use disorder (SUD), increases the likelihood of concurrent depression. Recent studies emphasize the interaction between genetic, environmental, and psychological factors. Family history remains a strong predictor of major depressive disorder (MDD), independently of childhood adversities. Polygenic risk scores and multigenerational family history suggest that genetic vulnerabilities are distributed across multiple small-effect variants. The impact of ACEs can be particularly strong, often leading to a synergistic effect that elevates rates of MDEs. The timing and type of ACEs can influence risk trajectories, with certain adversities having a greater impact during specific developmental stages. Comorbidity with psychiatric disorders such as anxiety and obsessive-compulsive disorder signifies a substantial risk for depression, with previous or concurrent diagnoses markedly increasing the likelihood of MDD, regardless of gender (Bruffaerts et al., 2024; Gronemann et al., 2025; Zhang et al., 2023).

              Neuroticism is recognized both as a personality trait associated with increased depression risk and as a mediator for the effects of childhood adversity on later depressive symptoms. This trait interacts with both acute and chronic stressors, with altered brain reward processing linked to its effects (Crouse et al., 2024).

Comorbidities

Depression can adversely affect chronic diseases, decrease health outcomes, and increase the cost of treating these conditions. Depression is more likely to co-occur alongside chronic health illnesses such as diabetes, cancer, Parkinson’s disease, Alzheimer’s disease, heart disease, hypothyroidism, stroke, autoimmune conditions (e.g., multiple sclerosis), and HIV. Among veterans, depression is 3 to 5 times more likely for patients with posttraumatic stress disorder (PTSD) than those without PTSD (National Center for PTSD, 2022). Medical conditions may contribute biologically to depression; patients may become clinically depressed as a psychological response to their medical illness, prognosis, symptoms (e.g., pain), or interference with their independence and functional capacity. Medications taken to manage chronic medical diseases can trigger or exacerbate depressive symptoms. At other times, the co-occurrence of depression and a medical condition may be unrelated. Regardless of etiology, the symptoms of depression often go undiagnosed in patients with co-occurring medical conditions, as they are either masked by the illness or discounted by patients, families, and healthcare providers (HCPs) as a normal emotional response to a health condition. The reverse may also be true, as patients with depression are at higher risk of developing certain physical illnesses, including diabetes, stroke, pain syndromes, and cardiovascular disease. While the etiology is not entirely understood, researchers postulate that this relationship is multifactorial and a by-product of poorer access to medical care and challenges with caring for oneself due to the symptoms of the underlying depression (e.g., nonadherence to prescribed medication regimens, poor eating habits, lack of exercise, substance use). Furthermore, several physiological alterations in body functioning have been identified in depressed patients, such as increased inflammation, changes in heart rate and blood pressure, and abnormalities in stress hormones; these can intensify the severity of comorbid conditions (American Psychiatric Association [APA], 2022; NIMH, 2024a, 2024b).

Complications: Suicide

Depression is linked to many complications, the most significant of which is suicide. Both depression and the medications used to treat depression increase an individual’s risk of suicide. HCPs must screen all individuals with depression for suicide. Worldwide, over 700,000 people die by suicide each year, making it the third leading cause of death among individuals ages 15 to 29 (World Health Organization, 2025). In 2023, more than 49,000 people died by suicide in the United States, which equates to about one death every 11 minutes. Beyond these tragic losses, suicidal thoughts and behaviors affected millions more adults: an estimated 12.8 million seriously considered suicide, 3.7 million made a specific plan, and 1.5 million attempted suicide. These numbers highlight not only the devastating toll of suicide deaths but also the much larger population struggling with suicidal ideation and crises, underscoring the urgent need for prevention, support, and accessible mental health care (Centers for Disease Control and Prevention [CDC], 2025; NIMH, 2025). Recent data from the CDC and analyses using CDC WONDER indicate that suicide remains a leading cause of death among individuals with MDD (Abdullah et al., 2025). From 1999 to 2022, the age-adjusted mortality rate (AAMR) for suicide among those with depressive disorders increased until 2015 and then stabilized, with men (AAMR: 10 per 1,000,000) consistently exhibiting higher rates than women (AAMR: 3.9 per 1,000,000) (Abdullah et al., 2025). The highest rates were observed in the 50–59 age group (AAMR: 11.2), among non-Hispanic White individuals (AAMR: 9.9), and in rural areas (AAMR: 12.5) compared to urban areas (AAMR: 5.4) (Abdullah et al., 2025). Epidemiological studies show that suicidal ideation and attempts are highly prevalent in MDD. In the United States, among adults with a past-year MDE, the proportion reporting suicidal ideation increased from 26.2% in 2009 to 32.5% in 2020, and suicide attempts rose from 2.7% to 3.3% over the same period (Bommersbach et al., 2023).

In 2023, the suicide rate among males was about four times higher than among females. The “Suicide Mortality in the United States, 2002–2022” data brief shows: For males, rates declined in younger age groups (10–14, 15–24) from 2020 to 2022 but increased in older age brackets (25+). For females, rates also increased in most older age groups (25–44, 45–64, 65–74, 75+) between 2020 and 2022. Younger female age groups (10–14, 15–24) had less change or stable rates in many cases. In 2022, among males, the highest suicide rate was in the 75 and older age group. Among females, the highest suicide rates were in middle-aged groups (45–64 years), although rates are increasing in the older age groups too (Garnett & Curtin, 2024).

Among adolescents aged 15 to 19, suicide rates have increased since 2012, rising from 8.4 to 10.5 per 100,000 deaths. Native Americans/Alaska Natives are the most prominently affected adolescent subgroup (37.2 per 100,000 deaths). Adolescent males are affected by over 3 times more than females (15.6 per 100,000 male deaths compared to 5.1 per 100,000 female deaths; United Health Foundation, n.d.). The Substance Abuse and Mental Health Services Administration’s (SAMHSA’s) 2024 National Survey on Drug Use and Health revealed an increasing prevalence of MDEs among adolescents, which corresponds to the rise in suicide deaths among them. The number of adolescents (age 12–17) who reported symptoms of MDEs in the past year increased from 5.5% (1.4 million people) in 2006 to 15.4% (3.8 million people) in 2024 (SAMHSA, 2025; Wolf et al., 2024).

During the lifetime of an individual experiencing MDD, over 46% express a desire to die, and over 39% contemplate suicide. Self-injurious behavior accompanied by an intent to die is classified as a suicide attempt. This means HCPs and society should err deliberately on the side of caution by classifying debatable behaviors as suicidal. While males are more likely to die by suicide, there are three female suicide attempts for every male suicide attempt. Still, it is challenging to determine the exact number of attempted suicides in the United States due to a lack of all-inclusive databases or tracking mechanisms. Data are primarily compiled through self-reported surveys and ICD-10-CM billing codes. Due to the high stigma associated with suicide attempts, they are vastly underreported (Drapeau & McIntosh, 2025; SAMHSA, 2025). According to SAMHSA (2025), 14.3 million Americans aged 18 or older reported seriously thinking about suicide, 4.6 million made a suicide plan, and 2.2 million attempted suicide in 2024. These numbers translate into a suicide attempt every 23 seconds and 25 attempts for every death by suicide across the nation (100–200:1 for young adults and 4:1 for older adults). People with a history of suicidal behavior or past suicide attempts face a significantly higher risk of dying by suicide later. About 7–13% of individuals who survive a suicide attempt eventually die by suicide, and as many as 7% of patients with MDD receiving specialized psychiatric care ultimately die from suicide (Lundberg et al., 2023).

The National Action Alliance for Suicide Prevention (Action Alliance) and the Suicide Prevention Resource Center proposed the Zero Suicide (ZS) Model, which provides a framework to coordinate a multilevel approach to implementing evidence-based practices. ZS encourages HCPs to screen all patients for suicide risk on their first contact with an organization and at each subsequent encounter. The core elements of the ZS model include ongoing risk assessment, collaborative safety planning, evidence-based interventions specific to the identified risk level, lethal-means reduction, and continuity of care. Structuring a suicide risk assessment is not straightforward and involves asking tough questions about suicidal ideation (i.e., thinking about, considering, or planning suicide) and prior attempts. Individuals may openly respond to queries and engage in discussions, or they may be limited in their replies and offer minimal information. Sometimes, a patient may bring up the topic on their own, but research demonstrates that this is rare (Ahmedani et al., 2025; Education Development Center, n.d.).

The following list outlines the assessment of risk for suicide as compiled and adapted from the Action Alliance (2018); and the National Strategy for Suicide Prevention (US Department of Health and Human Services [HHS], 2021, 2024) guidelines:

• A suicide risk assessment should consider risk and protective factors that may increase or decrease the patient’s risk of suicide.
• The observation and reporting of warning signs and evaluation of suicidal thoughts, intent, behaviors, and other risk and protective factors should inform any decision about a referral to a higher level of care.
• A person’s mental state and suicidal ideation can fluctuate considerably over time. People at risk for suicide should be reassessed regularly, especially if their circumstances have changed.
• The HCP should observe the patient’s behavior during the clinical interview. Disconnectedness may indicate an increased risk for suicide.
• The HCP should remain both empathetic and objective. A direct, nonjudgmental approach allows the HCP to gather the most reliable information collaboratively and encourages the patient to accept help.

To assess a patient’s suicidal thoughts, the HCP should inquire directly about thoughts of dying by suicide or feelings of engaging in suicide-related behavior. HCPs should be direct when inquiring about any current or past thoughts of suicide and ask individuals to describe such thoughts. According to Action Alliance (2018) and HHS (2024), a comprehensive evaluation of suicidal thoughts should include the following:

• onset (when did it begin)
• duration (acute, chronic, recurrent)
• intensity (fleeting, nagging, intense)
• frequency (rare, intermittent, daily, unabating)
• passive or active nature of the ideation (“wish I were dead” vs. “thinking of killing myself”)
• whether the individual wishes to kill themselves or is thinking about or engaging in potentially dangerous behavior, such as cutting, to relieve emotional distress
• lethality of the plan (no plan, overdose, hanging, firearm)
• triggering events or stressors (relationship, illness, loss)
• what intensifies the thoughts
• what distracts the thoughts
• association with states of intoxication (i.e., if thoughts are triggered only when the individual is intoxicated)
• understanding the consequences of future potential actions (Action Alliance, 2018; HHS, 2024; SAMHSA, 2017)

To assess suicidal intent, an HCP should appraise past or present evidence (implicit or explicit) that an individual wishes to die or means to kill themselves and understands the probable consequences of their actions or potential actions (Action Alliance, 2018; HHS, 2024; SAMHSA, 2017). The evaluation of intent to die should be characterized by the following:

• strength of the desire to die,
• strength of the determination to act, and
• strength of the impulse to act or the ability to resist the impulse to act (Action Alliance, 2018; HHS, 2024)

These factors may be highlighted by inquiring about how much the individual has thought about a lethal plan, can engage in that plan, and is likely to carry out the plan. To assess for preparatory behavior, the HCP should evaluate whether the patient has begun to prepare for self-directed violence, such as assembling a method or preparing for death (Action Alliance, 2018; HHS, 2024; SAMHSA, 2017). In addition to obtaining collateral information from the patient’s family members, medical records, and therapists, HCPs should assess preparatory behaviors by inquiring about the following:

• mentally walking through the potential attempt
• researching methods online
• thoughts about the location they would consider and the likelihood of being found or interrupted
• seeking access to lethal means or exploring the lethality of means, such as:
  • walking to a bridge
  • handling a weapon
  • acquiring a firearm or ammunition
  • hoarding medication
  • purchasing a rope or blade
• taking action or other steps in preparing to end one’s life, such as:
  • writing a will or suicide note
  • giving away possessions
  • reviewing a life insurance policy (Action Alliance, 2018; HHS, 2024; SAMHSA, 2017)

A risk assessment for suicide should include information from the patient and other sources about previous suicide attempts and the circumstances surrounding the event (e.g., triggers, the method used, consequences of behavior, and the role of substance use) to determine the lethality of any previous attempt (Action Alliance, 2018; Education Development Center, n.d.; SAMHSA, 2017). HCPs should inquire about the following:

• whether the attempt was interrupted by the patient or another person
• whether there was evidence of an effort to isolate or prevent discovery
• whether there have been multiple attempts (Action Alliance, 2018; Education Development Center, n.d.; SAMHSA, 2017)

For patients with a history of self-interrupted suicide attempt(s), obtain additional details to determine factors that enabled the patient to resist the impulse. A comprehensive suicide risk assessment requires a validated, evidence-based screening tool consisting of a set of directed questions. Examples of screening tools include the Columbia Suicide Severity Rating Scale (C-SSRS), the Suicide Assessment Five-Step Evaluation and Triage (SAFE-T), the Patient Safety Screener (PSS-3), and the Patient Health Questionnaire (PHQ). Evaluating the risk level and appropriate actions for each risk level is a critical aspect of suicide prevention. HCPs must understand how to perform a proper risk assessment, ascertain risk level, and respond according to evidence-based guidelines (Action Alliance, 2018; Education Development Center, n.d.). For more information, please refer to the NursingCE course on Suicide Prevention.

Signs and Symptoms of Depression

There are several types of depression, each with unique features and onset mechanisms, yet consistent signs and symptoms are recognized across all facets of depressive disorders. Depression substantially impairs day-to-day activities (e.g., work or school) and a person’s ability to cope with daily life. It can be long-lasting or recurrent, and those affected may have multiple physical symptoms with no apparent physiological cause (APA, 2022; Gaynes, 2025). The most common signs and symptoms of depression include the following:

• a loss of interest or pleasure in hobbies and activities
• a persistently sad, anxious, or “empty” mood
• feeling hopeless or having a pessimistic attitude
• changes in appetite or weight
• sleep disturbances
• irritability, agitation, or restlessness
• fatigue
• moving or talking slowly
• feelings of low self-worth, guilt, or shortcomings
• difficulty concentrating
• suicidal thoughts, intent, or attempts (APA, 2022; Gaynes, 2025)

Depression differs from sadness or bereavement and is outside the normal grieving process. While grief can be a trigger for depression, it does not cause depression. Children and adolescents experiencing depression have higher risks of being diagnosed with MDD as adults. Children with depression often present differently than adults. Behaviors may include avoidance of others, refusal to attend school, pretending to be sick, remaining at the parent’s side in social situations, mood swings, getting into trouble at school, or irritability. Since some of these behaviors are common in adolescents, diagnosing depression in this age group can be challenging. It can be equally difficult to diagnose depression in older adults. Signs and symptoms of dementia (e.g., agitation, irritability, and fatigue) can mimic depression. Those with dementia are also less likely to have feelings of helplessness or hopelessness that a depressed individual often experiences (APA, 2022; Gaynes, 2025).

Classification of Depression

The Diagnostic and Statistical Manual of Mental Disorder, 5th edition Text Revision (DSM-5-TR), states that all depressive disorders include a sad, empty, or irritable mood, alongside somatic and cognitive changes that significantly impact the patient’s functional capacity. Their major distinctions are limited to symptom duration, timing, or presumed etiology. Table 1 briefly describes the clinical presentation of the main subtypes of depression. Although there are different forms of depression, MDD is the classic form diagnosed and referred to when using the general term depression. This form will be discussed later in this module (APA, 2022; Gaynes, 2025).

Table 1

Depression Subtypes*

Depression Subtype	DSM-5-TR Description
Persistent depressive disorder (PDD), also known as dysthymia	A more chronic form of depression characterized by the following: a poor disposition characterizes this disorder, present most days for most of the day for 24 months or more in adults. this should not include any asymptomatic periods lasting longer than 8 weeks. the disposition may be cantankerous and crabby in adolescent and pediatric patients for 12 months or more. in addition to the poor disposition, at least two of the following co-occur: changes in sleep, resulting in poor sleep or excessive sleep a decreased sense of self-worth and self-regard a sense that nothing good will happen and that the current situation will never improve changes in food intake or interest, resulting in no desire to eat or eating significantly more than typical a sense of being tired or worn out despite adequate rest or sleep, without much drive or vigor poor decision-making or an inability to maintain focus The patient should not exhibit symptoms meeting the diagnostic criteria for a manic or hypomanic episode. The patient may exhibit symptoms meeting the diagnostic criteria for an MDD for 24 months. A separate diagnosis of MDE or MDD should also be documented in this case. A specifier should be added to the persistent depressive disorder of with persistent major depressive episode or with intermittent major depressive episodes, with/without current episode. The symptoms are not more appropriately due to another condition, such as a psychotic disorder (e.g., schizophrenia, schizoaffective DO, delusional disorder). The symptoms are not directly related to the use of a substance, medication, or preexisting medical diagnosis or health concern The symptoms cause substantial anguish or drastically affect the patient’s ability to function professionally, socially, or otherwise
Substance/medication-induced depressive disorder	Depression-like phenomena caused by substance use, inappropriate use of prescription medications (e.g., opioids), or illicit drug use Characterized by a consistent poor disposition or substantial decrease in enjoyment in nearly all activities. The symptoms must have presented in the midst of or following exposure to the implicated medication or substance (including withdrawal) The implicated medicine/substance has been known to cause the patient’s signs and symptoms Symptoms cause substantial anguish or dysfunction in at least one environment (work, home, social settings) Symptoms are not only present with acute delirium The symptoms are not due to a more appropriate mood disorder, as evidenced by the satisfaction of the following features: initial symptom presentation prior to substance exposure symptom duration for longer than expected (e.g., 4 weeks) a past episode of similar symptoms not associated with substance use If the mood-related symptoms are mild and clinically insignificant, a diagnosis of substance intoxication or withdrawal may be more clinically appropriate
Disruptive mood dysregulation disorder	The patient being evaluated for this diagnosis should be between the ages of 6 and 18, and symptoms should be observable by age 9 at the latest. This condition is defined by tantrums or fits that are extreme and repeated, vocal or bodily, and the inciting situation is insignificant in comparison to the patient’s reaction. The tantrums and fits are not in alignment with the patient’s age or ability. The patient experiences tantrums at least three times per week. The patient’s demeanor between the tantrums is consistently cantankerous or mad throughout the day most days; this is objectively obvious to those around them. The four characteristics described previously have been observable for at least a year without more than 12 consecutive asymptomatic weeks. The four characteristics described previously can be observed in more than one of the following environments and considered extreme in one or more: participating in academics, engaging socially with friends, or interacting in their house with family The patient has not displayed symptoms that qualify as a manic or hypomanic episode (see separate criteria) lasting for more than 24 hours The symptoms are not more appropriately related to another condition, namely, separation anxiety disorder, MDD/PDD, PTSD, autism spectrum disorder The patient’s symptoms are not directly related to the use of a substance, medication, or preexisting medical diagnosis or health concern * This condition should not be diagnosed in patients with intermittent explosive disorder, bipolar disorder, or oppositional defiant disorder (ODD). However, it may occur concurrently with attention-deficit/hyperactivity disorder (ADHD), SUD, conduct disorder, or MDD. This diagnosis typically displaces a prior diagnosis of ODD, and a diagnosis of bipolar disorder often displaces a prior diagnosis of disruptive mood dysregulation disorder.
Premenstrual dysphoric disorder	Hormone-induced depression in female patients that markedly impacts daily functioning. The criteria include the following: Five or more of the following symptoms must occur during the last week prior to menstruation in most menstrual cycles in the previous 12 months. The symptoms gradually abate during menses and should be insignificant or nonexistent during the following week. The symptoms must include at least one from group B and one from group C: Group B: a significant cantankerous mood, feeling mad or fighting with family/friends often a significant concern, worry, strain, nervousness, or tenseness significant quick changes in mood, with rapid shifts between highs and lows, or feeling a heightened level of emotional susceptibility a substantial decrease in disposition, with a sense that nothing good will happen and that the current situation will never improve, or poor self-regard Group C: an inability to maintain focus changes in food intake or interest, resulting in no desire to eat or eating significantly more than typical a lack of control or feeling overcome, that circumstances are more than the patient can handle a reduced desire to participate in behaviors they previously enjoyed (friends, interests, etc.) a sense of being tired or worn out despite adequate rest or sleep, without much drive or vigor changes in sleep, resulting in poor/lack of sleep or excessive sleep subjective discomfort, including arthralgia, myalgia, increase in weight, breast discomfort, or a sense of fullness or tightness in the abdomen The symptoms should be tracked by the patient for two consecutive cycles to document and confirm the diagnosis The symptoms must cause substantial anguish or drastically affect the patient’s ability to function professionally, socially, or otherwise The symptoms are not directly related to the use of a substance, medication, or preexisting medical diagnosis or health concern The symptoms are not more appropriately due to an exacerbation of another mood condition, such as PDD, MDD, a personality disorder, or panic disorder, although these may be diagnosed simultaneously.
Bipolar disorder	Bipolar I is characterized by periods of extreme highs (i.e., mania) that may be interspersed with episodes of MDE. Bipolar II is characterized by episodes of extremely low mood (i.e., meeting the criteria for MDE) accompanied by periods of moderate highs (i.e., hypomania). This condition was previously referred to as manic depression.
With peripartum onset (previously, postpartum depression)	The symptoms used to diagnose the patient with an MDE began while the patient was pregnant or within 28 days of delivery. These symptoms may include psychotic features, such as delusions or hallucinations. This is more common in those with a prior history of similar episodes, those with a history of a mood disorder or bipolar I disorder, those with a family history of bipolar disorder, and first-time mothers. These symptoms should be carefully differentiated from delirium, which may occur in the postpartum period due to lack of sleep. This is characterized by a changing level of consciousness and a poor ability to focus. By contrast, maternity blues (or baby blues) is self-limited, and even without treatment, it often resolves within a week as hormone levels stabilize. It is characterized by rapid fluctuations in mood, sleep disruption, or mental bewilderment but does not lead to dysfunction.
With seasonal pattern (previously seasonal affective disorder)	The patient’s symptoms meet the diagnostic criteria for MDD/E The symptoms follow a consistent pattern that corresponds with the seasons, most often with an increase in symptoms from September through March Symptoms remit (typically in the spring) and remain minimal or absent through the remainder of the year (typically from March through September) The pattern of clinically significant symptoms during one to two seasons and full remission during the remainder of the year has been consistent for the prior 24 months
With psychotic features	characterized by MDE alongside concurrent psychotic symptoms (e.g., delusions or hallucinations) psychotic symptoms may have a “theme,” such as guilt, mortality, or illness (mood-congruent) or not (mood-incongruent)

 (APA, 2022; Gaynes, 2025)

*This is a summary of the diagnostic criteria detailed in the DSM-5-TR; to make an actual diagnosis, the provider should reference the diagnostic guidelines listed in the DSM-5-TR for each depression subtype.

Depression Screening

The US Preventive Services Task Force (2022, 2023) suggests screening for depression in all adults and adolescents. Depression is associated with a lower quality of life, compromised interpersonal relationships, decreased work performance, and loss of life through suicide, increasing the urgency for proper recognition and diagnosis (US Preventive Services Task Force, 2022, 2023).

Best-practice guidelines recommend initially screening individuals for depression using the PHQ-2. The PHQ-2 asks the following priority questions (APA, 2022; HHS, 2021; Williams & Nieuwsma, 2025).

• Over the past 2 weeks, how often have you been bothered by any of the following problems?
  • little interest or pleasure in doing things
  • feeling down, depressed, or hopeless

Patients who respond “yes” to either question on the PHQ-2 should undergo additional screening with the PHQ-9, a multipurpose, 9-item symptom checklist used to screen for, diagnose, monitor, and measure the severity of depression. The PHQ-9 incorporates the DSM-5-TR diagnostic criteria for depression and a question that screens for the presence and duration of suicidal ideation (APA, 2022). The tool is brief, easily used in clinical practice, and rapidly scored. It is also useful for monitoring the improvement or worsening of symptoms. Each question has four answers: “not at all,” “several days,” “more than half the days,” and “nearly every day” (Chung et al., 2023; Kroenke et al., 2001) The questions are as follows:

Over the last 2 weeks, how often have you been bothered by:

• little interest or pleasure in doing things?
• feeling down, depressed, or hopeless?
• trouble falling or staying asleep, or sleeping too much?
• feeling tired or having little energy?
• poor appetite or overeating?
• feeling bad about yourself or that you are a failure or have let yourself or your family down?
• trouble concentrating on things, such as reading the newspaper or watching television?
• moving or speaking so slowly that others could have noticed, or being so fidgety/restless that you have been moving more than usual?
• thoughts you would be better off dead or of hurting yourself? (Chung et al., 2023; Kroenke et al., 2001)
• 
  

The PHQ-9 scoring categories are as follows: 5–9 (mild), 10–14 (moderate), 15–19 (moderately severe), and 20–27 (severe). These categories align with current clinical practices and correspond to the symptom criteria and severity levels outlined in the DSM-5-TR for MDEs. The items on the PHQ-9 directly relate to the diagnostic criteria in the DSM-5-TR, and the tool has been validated for use among adults, adolescents, and older adults, including versions available in Spanish and other languages. It is important to note that a positive result on the PHQ-9 should always be followed by a clinical interview to confirm the diagnosis and evaluate any functional impairment (APA, 2022; Williams & Nieuwsma, 2025).

Table 2

Severity Level of Depression

Severity	PHQ-9 Total Score
No Depression	0–4
Mild	5–9
Moderate	10–14
Moderate-severe	15–19
Severe	20–27

(APA, 2022; Williams & Nieuwsma, 2025)

The PHQ-9 is an effective screening tool for MDD, with meta-analyses indicating a sensitivity and specificity of around 85% when using a standard cutoff score of 10. However, due to its high sensitivity, there is a possibility of false positives, and a positive score alone does not confirm a diagnosis of depression. Current guidelines recommend using the PHQ-9 as part of a two-step approach: first, an initial screening followed by a comprehensive clinical assessment to establish a diagnosis and determine treatment options. Clinicians are encouraged to interpret PHQ-9 scores within the context of the patient’s overall medical, psychiatric, and psychosocial history. This ensures that screening is effectively connected to appropriate evaluation, follow-up care, and treatment planning. In addition to the PHQ-9, nurses should be mindful of any acute safety risks (e.g., harm to self or others, psychotic features) and assess each patient’s functional status, medical history, past treatment, and family history. While the tool is practical and validated for the screening of patients for potential depression, most contend that the PHQ-9 is an insufficient assessment tool for suicide risk and suicidal ideation compared to other suicide-specific tools, such as the Columbia-Suicide Severity Rating Scale (C-SSRS) and the Suicide Assessment Five-Step Evaluation and Triage (SAFE-T; Chung et al., 2023; Williams & Nieuwsma, 2025). Additional depression screening tools frequently used in primary care are listed in Table 3.

Table 3

Screening Tools

Screening Tool	Description
Beck Depression Inventory	21-Question multiple-choice test Focuses on identifying and measuring the severity of depression
Hamilton Depression Inventory	17-Question test to evaluate a patient’s mood A higher score is associated with MDD
Geriatric Depression Scale	Designed for older adult patients Does not work well for those with dementia

(APA, 2023a; Williams & Nieuwsma, 2025)

Diagnosis

MDD is defined by the presence of at least one MDE in an individual with no history of mania or hypomania. Based on high-quality evidence, the APA (2022) strongly recommends that clinicians use the DSM-5-TR criteria to determine a diagnosis of MDD, MDE, and other specified or unspecified depressive disorders. The DSM-5-TR outlines the required diagnostic criteria for a diagnosis of MDD, as summarized in Table 4. Of note, criteria A through C represent an MDE. These symptoms must be new for the individual or worsening of an existing symptom and must be present over 2 weeks. A diagnosis requires a thorough interview, as individuals often circumvent direct questioning when discussing their mood. For some patients, symptoms of MDD can present as a physical manifestation (e.g., pain). Other patients may report feelings of agitation or anger, rather than sadness. This is often true in adolescents and children who may present as irritable or cranky instead of sad or dejected. A diagnosis can be complicated if the individual has a concurrent disease that can produce similar symptoms (e.g., cancer, diabetes, or pregnancy; APA, 2022; Gaynes, 2025).

Table 4

DSM-5-TR Diagnostic Criteria for MDD

Criterion A (at least five signs required over a period of at least 14 days)	The presence of either (a) lack of interest/enjoyment or (b) depressed mood, in addition to the following: significantly reduced interest or enjoyment in most activities for the majority of the day, practically every day, self-reported or observed poor or sad mood for the majority of the day most days; may be based on tearfulness observed by others or self-reports of unhappiness, unfulfillment, or despondency psychomotor excitement or delay most days; must be obvious to others, not solely a self-report of symptoms reduced mental clarity, focus, or decision-making almost every day feelings of insignificance or extreme, unwarranted guilt most days; may be unrealistic substantial (at least 5% of total body weight) unintentional decrease or increase in weight in a month the inability to sleep at night or stay awake during the day despite getting an adequate amount of sleep the night before most days feeling lethargic, weary, or exhausted most days a preoccupation with death, consistent suicidal ideations with or without a specific plan, or an attempted suicide
Criterion B	Symptoms create substantial anguish or dysfunction in essential settings, such as work, school, or around friends/family.
Criterion C	The symptoms are unrelated to the effects of a physical illness or substance use.
Criterion D	The symptoms are not more accurately attributed to another mental health diagnosis.
Criterion E	There is no history of a period of manic or hypomanic symptoms (unrelated to substance use or another physical illness).

(APA, 2022)

Note: This is an interpretive representation of the diagnostic criteria detailed in the DSM-5-TR; to make an actual diagnosis, the provider should reference the diagnostic guidelines listed in the DSM-5-TR.

While grief can trigger depression, it does not cause depression. Nurses should consider that personal responses to a significant loss (e.g., loss of a loved one, bereavement, financial ruin, or a serious medical illness) may include intense feelings of sadness or loss, insomnia, poor appetite, and weight loss (as outlined in Criterion A). Although such symptoms may be understandable or considered an appropriate reaction to a loss, the presence of an MDE in the setting of a significant loss should be carefully considered. This decision should be premised on clinical judgment and balanced according to the individual’s baseline functioning, history of expressing distress in the context of loss, and cultural norms (APA, 2022; Gaynes, 2025). A recent addition to the DSM, prolonged grief disorder cannot be diagnosed within 12 months of the death of the identified deceased individual (within 6 months in adolescents or children). The symptoms must cause substantial anguish or dysfunction, and the grief reaction extends beyond a period that would be considered typical

(APA, 2022; Gaynes, 2025).

Differential Diagnosis

Once screening has been completed with a risk identified, the clinician will determine a diagnosis of depression through further assessment. No definitive diagnostic test exists for depression; it is commonly a diagnosis of exclusion. The first step in diagnosing any mental health condition is ruling out underlying medical conditions. Conditions such as hypothyroidism, malignancy (e.g., brain tumor), or vitamin deficiency can mimic depression and should be ruled out before initiating treatment. Clinicians may consider ordering a urine or serum toxicology screening for patients with clinical suspicion of substance use. Imaging studies (computed tomography [CT] scan or magnetic resonance imaging [MRI]) may be indicated to rule out intracranial pathology. The physical examination of a depressed patient may be unremarkable; however, outward changes may be apparent, such as poor hygiene, a flat affect, slowed speech, weight loss, or psychomotor excitement or delay. Mental status should be assessed to rule out cognitive decline, particularly in older patients. The exam should include an assessment for delusions, hallucinations, or mood swings (APA, 2022; Gaynes, 2025).

Treatment

An individualized treatment plan should be developed using shared decision-making and will vary based on the patient’s severity level of depression (mild, moderate, moderate–severe, or severe). Treatment for depression may include counseling, therapy, and/or medication. Adequate treatment can prevent suicide related to depression. The most effective treatment for depression is a combination of psychotherapy with pharmacological treatment, such as antidepressant medication (Gartlehner et al., 2023; Rush, 2025a).

Psychotherapy

Psychotherapy is a successful, beneficial, and cost-effective treatment for depression. The APA (2023b) defines psychotherapy as any psychological service moderated by a trained professional (i.e., psychotherapist) that employs communication and interaction principles to assess, diagnose, and treat mental health disorders. Also referred to as talk therapy, psychotherapy is premised on establishing a supportive environment and collaborative relationship between a patient and a psychotherapist to foster open discussion in an objective, neutral, and nonjudgmental manner. A psychotherapist includes any individual professionally trained and licensed according to their respective governing state-licensing boards to treat mental health conditions (e.g., psychologist, psychiatrist, psychiatric nurse, APRN, counselor, therapist, or social worker). Research demonstrates that depressed individuals who receive psychotherapy achieve more durable treatment responses (i.e., are less prone to relapse) and better symptom control than when medication is used alone. Although psychotherapy is effective, it is underutilized and can be difficult to access at times, depending on location, and may not be covered or only partially covered by medical insurance. Most forms of psychotherapy can be performed in private offices, community centers, inpatient or outpatient treatment programs, US Department of Veterans Affairs (VA) facilities, counseling centers, and educational settings. Traditional psychotherapy involves in-person sessions, but a growing number of therapists are providing online (remote) therapy sessions, as demand has risen dramatically during the COVID-19 pandemic, with an increased reliance on technology. Research demonstrates that online psychotherapy has comparable efficacy to in-person approaches, and this continues to be a topic of investigation as more patients opt for online therapy (APA, 2019, 2023b; Luo et al., 2020; Rush, 2025a, 2025c). For more information on delivering patient care remotely, see the NursingCE course on telemedicine.

While there are several types of psychotherapy, the most effective options for depression include cognitive-behavioral therapy (CBT), mindfulness-based cognitive therapy (MBCT), problem-solving therapy (PST), behavioral activation (BA), and interpersonal therapy (IPT). Each patient and psychotherapist is encouraged to set mutually agreed upon and realistic goals that are periodically reevaluated. Patient response varies based on the presenting issue, severity, complexity, interference with functioning, openness to receiving treatment, and specific interventions. If patient improvement does not occur within the planned duration of treatment, the intervention should be reassessed, and other therapeutic strategies should be considered. There is no universally effective approach to treating depression. Experienced psychotherapists typically blend modalities and tailor the treatment to meet each patient’s specific needs, often adjusting the treatment course as underlying issues are revealed during the patient’s progress through therapy (APA, 2019, 2023b; Rush, 2025a; Wampold, 2019).

Cognitive Behavioral Therapy

CBT is among the most well-cited and established forms of psychotherapy, as it has the most rigorous evidence supporting its clinical utility. It is often referred to as the gold standard of psychotherapy, as other forms have not demonstrated superior efficacy.

Primary Uses. CBT was initially utilized for managing depression and was the first psychotherapy identified as evidence-based in most clinical guidelines. In addition to treating depression, CBT has demonstrated effectiveness for several other conditions, including anxiety, trauma (e.g., PTSD, childhood trauma, and sexual trauma), SUDs, eating disorders, and couples’ discord. CBT may also help manage certain aspects of psychosis (e.g., psychotic episodes, schizophrenic delusions) and is validated across diverse demographics, including veterans and active service members. The overarching features of CBT include short-term, problem-focused, cognitive, and behavioral interventions. It is not a one-size-fits-all model, as there are several variations. CBT teaches patients to restructure cognitive distortions and self-defeating behaviors and replace them with more accurate thoughts and functional behaviors. The focus is narrowed to each patient’s current problem(s) to provide practical solutions and strategies to manage them successfully. The specific intervention(s) employed will depend on the underlying issue. Patients are encouraged to apply new behaviors to real-life settings, allowing them to practice skills during the therapeutic relationship to troubleshoot new behaviors and obtain feedback from the psychotherapist. Patients learn to track their thoughts and activities to identify the affective and behavioral consequences during debriefing sessions with their psychotherapist. CBT is time-limited and typically consists of 8 to 16 sessions. In addition to face-to-face and telephone sessions, CBT can also be administered via computer-based programs, which are known as computer-based CBT (Cuijpers et al., 2025; Luo et al., 2020; Lebow, 2025).

CBT-Insomnia (CBT-I). Insomnia and depression commonly coexist, and CBT-I is recommended as a first-line treatment for affected patients. CBT-I is a multicomponent approach targeting behaviors and thoughts that interfere with sleep. In a recent systematic review and meta-analysis, Feng and colleagues (2020) found CBT-I to be safe, effective, and superior to no treatment for insomnia. CBT-I may be delivered face-to-face in individual or group settings over an average of 4 to 8 sessions. This approach incorporates sleep hygiene principles, including:

• establishing a consistent bedtime routine
• abstaining from substances like caffeine after lunch or alcohol and nicotine before bed
• avoiding activities that interfere with sleep (e.g., vigorous exercise) within 2 to 3 hours of sleep
• eliminating daytime sleeping
• optimizing the sleep environment
• creating a consistent bedtime and wake time
• limiting the time spent in bed to established sleep times (i.e., sleep restriction; Winkelman, 2025)

Patients are advised to create a 2-week sleep log documenting their sleep habits, and the CBT-I approach is individualized based on the information recorded in the log. The time spent asleep should be added to half of the time spent awake in bed, yielding the prescribed sleep restriction. This time should never be under 5 hours. Once the patient sleeps for at least 80% of the specified time for 7 consecutive days, the prescribed sleep restriction should be increased by 20 minutes for the following week (Winkelman, 2025).

Mindfulness-Based Cognitive Therapy

MBCT is a more recent form of CBT developed by the collaborative efforts of Zindel Segal, Mark Williams, and John Teasdale. The first clinical trial data were not published until the beginning of the 21st century. MBCT was initially developed as a relapse-prevention treatment for depression that encouraged patients to change their function rather than the content of negative thoughts. Patients with a history of depression experience a poor mood, negative memories, and unhelpful cognitive patterns, triggering the reoccurrence of depressive symptoms. Several randomized controlled trials (RCTs) have demonstrated the clinical utility and efficacy of MBCT for patients with depression who have endured multiple relapses. In a 2020 systematic review and meta-analysis by McCartney and colleagues (2020), including 14 RCTs (n=2,077), MBCT showed a statistically significant advantage over treatment as usual (TAU) and the placebo group in preventing depression relapse. Researchers determined that MBCT was more effective than TAU in the long-term prevention of depression relapse and had statistically significant advantages over TAU and placebo regarding the time to relapse (McCartney et al., 2020). It has also been successfully applied to patients with chronic pain conditions (e.g., fibromyalgia). Furthermore, studies have also demonstrated that it has yielded improvements in overall well-being when applied to patients with chronic illnesses such as cancer, heart disease, or diabetes (Cuijpers et al., 2025; Segal, 2025).

MBCT helps patients focus on the present in a nonjudgmental and accepting manner. It does not seek to modify or eliminate dysfunctional thoughts. Instead, it focuses on assisting patients to become more detached and observe their thoughts objectively without necessarily attempting to change them. MBCT focuses on developing mindfulness through meditation, imagery, experiential exercises, and relaxation techniques (Cuijpers et al., 2025; Segal, 2025).

MBCT teaches patients to view themselves as distinct from negative thoughts by employing cognitive methods and meditation to interrupt the automatic processes that re-trigger these feelings. This approach emphasizes changing one’s reaction to unwanted thoughts, not the content of the thoughts themselves. A judgment of undesirable cognitions creates powerful secondary emotions (e.g., low mood, hopelessness, sadness). Through MBCT, patients learn to distance themselves from these thoughts by becoming more aware of how they practice judgment. Mindfulness teaches patients to break this cycle by continually refocusing on making deliberate choices to improve how they critique their thoughts. While the delivery of MBCT varies, it is primarily used in a group setting, with weekly sessions lasting 60 to 120 minutes for 8 weeks. Group sessions are accompanied by 30- to 45-minute homework assignments six times per week. Homework assignments help patients develop and practice mindfulness meditation techniques, usually through audio or video recordings. Since the definition of mindfulness can vary across clinical applications, it is difficult to conceptualize a model of mindfulness meditation that applies to all patients; therefore, most sources describe this concept as the practice of developing a deeper awareness of one’s mind and body without judgment in the present moment. Specific strategies may include yoga, breathing meditations, and exercises (Dimidjian et al., 2023; Gkintoni et al., 2025).

Problem-Solving Therapy

PST is a structured cognitive-behavioral intervention that strives to improve a person’s ability to prevent and cope with stressful life experiences by equipping them with various affective, cognitive, and behavioral tools. PST focuses on developing specific coping skills for problem areas and is particularly effective for stress management and depression. Most sources describe PST as a type of CBT-based psychotherapy, but some argue that problem-solving is the core of PST and that cognitive restructuring is often omitted. PST is a highly examined psychotherapeutic intervention for managing depression in adults and is comparable to other psychological treatments for depression. PST has also demonstrated efficacy in managing anxiety disorders, including phobias (e.g., social phobia, agoraphobia), HIV risk behaviors, drug abuse, suicidal behaviors, childhood aggression, and conduct disorders (Lebow, 2025; Shang et al., 2021).

PST offers a flexible therapeutic approach and is employed in a group setting or on an individual basis. It is often used as part of a larger treatment plan, helping patients overcome barriers associated with nonadherence to medical or psychological treatments (e.g., adhering to a weight-loss program or medication compliance). Patients engage in active problem-solving activities through a collaborative relationship with a psychotherapist. Specific PST interventions include psychoeducation, interactive exercises that train critical thinking skills, homework assignments, and practice opportunities. Patients learn to identify and prioritize key problem areas, breaking them down into manageable tasks to develop effective coping behaviors and solutions. PST focuses on empowering patients to learn how to solve problems on their own. Depending on the patient’s needs, therapy may range from 4 to 12 individual sessions, with an average duration of 45 to 60 minutes per session. While there are different styles of PST, they are all premised on the same principle of resolving depression by engaging patients in active problem-solving activities (Lebow, 2025; Zhang et al., 2018). PST typically involves the following seven stages:

• selecting and defining the problem
• establishing realistic and achievable goals for problem resolution
• generating alternative solutions
• implementing decision-making guidelines
• evaluating and choosing solutions
• implementing the preferred solutions
• evaluating the outcome (Lebow, 2025; Zhang et al., 2018)

 

Behavioral Activation

BA is chiefly indicated for those experiencing depression, presupposing that cognitions are sources of avoidance that sustain depressive symptoms. Research demonstrates that when people feel depressed, they tend to disengage from (or avoid) everyday routines and withdraw from social environments. Over time, avoidant behaviors worsen depression as people isolate themselves and lose opportunities for positive reinforcement. A Cochrane review of 53 RCTs involving 5,495 participants evaluated the effects of BA compared to other psychological therapies, medications, and treatments for depression in adults. Findings revealed no difference in short-term treatment efficacy between BA and CBT based on moderate-certainty evidence, but BA was more efficacious than medication therapy. Not enough data were available to compare BA directly with other forms of psychotherapy, specifically psychodynamic, interpersonal, and integrative therapies (Dimidjian, 2024; Uphoff et al., 2020).

BA targets the connection between behavior, feelings, and depression. BA is considered a critical and powerful CBT skill for treating depression. It helps patients understand how their behaviors influence their emotions and envision how they can control this process. BA seeks to increase behaviors that bring a patient into contact with positive reinforcements and decrease behaviors that impede this contact based on the assumption that action precedes emotions. Activation changes an individual’s brain state—a concept referred to as reinforcing positive context contingencies. The simplest example of this concept is engaging in cardiovascular exercise (e.g., running) to induce an endorphin release (i.e., endogenous chemicals produced by the body to relieve pain) into the bloodstream, which improves mood. The more an individual activates a specific behavior that derives a perceived benefit, the more situations they will expose themselves to that result in positive emotions. BA focuses on positive reinforcement by increasing a patient’s contact with rewarding and pleasant experiences and social activities. This approach also teaches patients how to identify processes that inhibit activation and encourage avoidant behaviors, thereby boosting critical thinking skills (Dimidjian, 2024; Uphoff et al., 2020).

BA is a well-established and evidence-based psychotherapy for depression, demonstrating efficacy comparable to CBT and surpassing treatment as usual or inactive controls in both primary care and specialty settings. The core components of BA include activity monitoring, scheduling activities that align with personal values, and increasing engagement in pleasurable and mastery-oriented behaviors. The emphasis on values (meaningful pursuits), pleasure (enjoyable activities), and mastery (actions that promote skill development and accomplishment) is central to the therapeutic benefits of BA. Treatment protocols for BA can vary from 1 to 24 sessions. BA Treatment for Depression (BATD) can be effective in as few as 6 to 15 sessions, especially in primary care or community settings. BA is effective in individual, group, and internet-based formats, providing flexibility in its delivery. Recent guidelines explicitly recognize BA as one of the most effective treatments for MDD in adults (Cuijpers et al., 2023; Dimidjian, 2024; Uphoff et al., 2020).

Brief BATD is a type of BA specifically designed to treat depression. The core components of BATD include the following:

• understanding the cyclic nature of depression
• identifying goals and values
• activity and mood monitoring (e.g., tracking moods across activities throughout the day, week, or month)
• building motivation and energy in a stepwise approach by incorporating pleasure and proficiency in skills
• activity scheduling (i.e., purposefully scheduling enjoyable and meaningful activities)
• reducing avoidant behaviors
• completing between-session assignments or tasks (e.g., meeting small-scale goals by practicing a target behavior (Cuijpers et al., 2023; Dimidjian, 2024; Uphoff et al., 2020)

Interpersonal Psychotherapy (IPT)

IPT is a structured, present-focused, evidence-based intervention for mood disorders that focuses on interpersonal difficulties that lead to psychological problems. IPT was designed as a brief, time-limited intervention for patients with depression, with the primary objective of improving relationships to alleviate symptoms. Although a specific event or relationship may not cause depression, depression commonly affects relationships and creates interpersonal problems (Swartz, 2023).

IPT is an adaptive and versatile treatment easily modified for disorders, demonstrating efficacy for SUD, bipolar disorder, and peripartum depression. Treatment is present-focused (e.g., on psychological difficulties sparked by recent conflicts or transitions), but aspects of attachment theory are used to analyze how past relationships affect current relationships. Attachment theory maintains that the relationship between a caregiver and an infant is crucial to survival and remains essential throughout life. A secure attachment early in life provides a solid foundation for psychological security and healthy intimacy in adult relationships. In contrast, early disturbances in attachment increase a person’s vulnerability to depression and other psychological difficulties, particularly in interpersonal relationships. IPT teaches patients to evaluate their interactions to build an awareness of how they relate to others. The short-term goals of IPT are to reduce symptoms and improve social adjustment, whereas the long-term goal is to help patients learn how to make necessary adjustments independently in the future (Swartz, 2023).

This approach targets the social and interpersonal context of a patient’s problems. IPT focuses on the present and highlights the patient’s interpersonal life in four problem areas:

• role disputes (conflicts with significant others, nonreciprocal expectations between individuals)
• interpersonal skill deficits (communication shortfalls, impaired social skills, social isolation, a series of unfulfilling relationships)
• grief over the loss (death of a close contact, loss of an intimate relationship)
• role transitions (changing roles, such as going from working to retiring or from married to divorced; Cohen et al., 2024; Swartz, 2023)

IPT is typically limited to 3 or 4 months (up to 20 sessions) and is organized into three session groups (opening, middle, and final). IPT can be administered as a sole form of therapy or in conjunction with medications. Most studies indicate that the combination of medication and IPT may be more beneficial than either method alone. Psychotherapists may employ techniques such as role-playing to help patients understand and adjust how they relate to their world (Swartz, 2023). For more information, refer to the NursingCE course on psychotherapy.

Complementary and Alternative Treatment

Complementary and alternative treatments can be used as an adjunct to other evidence-based treatments for depression. When combined with evidence-based treatment options, such as prescription medications and psychotherapy, these interventions can contribute positively to the overall treatment plan for depression. There are pharmacological agents available over the counter (OTC) for the management of depression, such as hypericum perforatum (St. John’s wort), omega-3 fatty acid (fish oil), and s-adenosyl methionine (SAM-e). However, these agents are not US Food and Drug Administration (FDA)–approved for depression, nor are they regulated by the FDA to ensure their safety and efficacy. The lack of FDA oversight and regulation of these agents poses concerns regarding the consistency of formulations, the purity of their ingredients, and safety profiles. Although patients do not require a prescription to obtain these drugs, they still pose a risk of significant adverse effects and dangerous drug interactions. Some complementary and alternative treatments with evidence of positive contributions to the treatment of depression are described in what follows (Cheng et al., 2025; National Center for Complementary and Integrative Health [NCCIH], 2021).

Exercise and Yoga

Exercise increases endorphins and stimulates the secretion of norepinephrine, which can improve a person’s mood. Low-intensity exercise over time stimulates the release of proteins that cause the nerve cells to grow and generate new connections. These processes improve brain function, support nerve cell growth in the hippocampus, and improve nerve cell connections, all of which alleviate depressive symptoms (Harvard Health Publishing, 2021; Rush, 2025c). Yoga is a mind and body practice founded in ancient Indian philosophy. It centers on achieving a relaxation response through spirituality and meditation, an integral component of yoga. Meditation is especially beneficial for reducing stress and depressive symptoms. Studies have shown that yoga and meditation positively benefit people with depression and other mental health conditions (NCCIH, 2021; Rush, 2025c). Numerous studies have evaluated the feasibility, efficacy, and tolerability of Sudarshan Kriya yoga (SKY) as an adjunctive intervention for patients with MDD. SKY is a breathing-based meditative technique that focuses on slow, medium, or fast rhythmic breathing cycles. It has been reported to decrease cortisol, increase prolactin, and improve antioxidant status. Their findings demonstrated that SKY helped alleviate severe depression in people who did not fully respond to treatment with antidepressants (Bhargav et al., 2021; Moosburner et al., 2024).

Light Therapy

              Bright light therapy (BLT) is a first-line, well-tolerated intervention for seasonal affective disorder (SAD), with robust evidence demonstrating improvements in depressive symptoms and functioning compared to placebo and other interventions. The most effective regimen is exposure to white light at 2,500–10,000 lux for 30–60 minutes daily, typically in the morning. BLT is recommended as either monotherapy or adjunctive therapy for SAD (Wang et al., 2025; Rush, 2025c).

              Recent meta-analyses and the 2022 US Department of Veterans Affairs and Department of Defense clinical practice guideline also recommend BLT for mild to moderate MDD regardless of seasonal pattern, citing evidence of improved response and remission rates. BLT is associated with a favorable safety profile, with only mild and transient side effects such as headache or eye irritation. In older adults, systematic reviews and meta-analyses confirm that BLT is effective in reducing depressive symptoms, particularly at higher intensities (≥10,000 lux) and when white light is used. BLT has also shown benefits for individuals with dementia and Alzheimer’s disease, improving mood, sleep, and neuropsychiatric symptoms. Overall, BLT remains a safe, effective, and accessible treatment for SAD, nonseasonal depression, and depression in older adults, with recent clinical guidelines and high-quality evidence strongly supporting its use (Wang et al., 2025).

 

Folate

Folate, also known as folic acid or vitamin B9, is an essential nutrient in green leafy vegetables and fortified grain products. Low folate levels have been associated with depression, as well as dementia. When folate levels are deficient, patients may not receive the full therapeutic effect of their prescribed antidepressant medication. Studies have shown that adding a methylfolate (the form of folate that crosses the blood brain barrier) can enhance the effectiveness of antidepressant medications without causing dangerous drug interactions. Furthermore, some studies have demonstrated that methylfolate supplementation may be an effective adjunctive therapy or a stand-alone treatment for reducing depressive symptoms and improving cognitive function (Gitlin, 2025; NCCIH, 2021).

Hypericum Perforatum (St. John’s Wort)

Hypericum perforatum (St. John’s wort) is a supplement with chemical properties similar to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), the two most prescribed classes of antidepressants. Nurses should warn patients not to take hypericum perforatum (St. John’s wort) with a prescribed antidepressant, as the combination causes increased levels of serotonin in the body, which can have mild to severe effects. Hypericum perforatum (St. John’s wort) is notorious for interacting with several other prescription medications (e.g., benzodiazepines, warfarin [Coumadin], digoxin [Lanoxin], hormonal contraceptives, and antiepileptics), either expediting or diminishing the metabolism of the prescribed agent, leading to reduced efficacy or higher toxicity. Because of the multiple interactions between St. John’s wort and many commonly used medications, the inconsistent evidence for efficacy and the lack of regulated dosing, it is not recommended for the treatment of depression (Gitlin, 2025; NCCIH, 2021; Saper, 2025).

 

Omega-3 Fatty Acids (Fish or Algae Oil)

Omega-3 fatty acids (fish or algae oil) have been widely studied for their benefits to cardiovascular health but have also been subject to significant research regarding their potential role in depression. Individuals who do not consume enough omega-3 fatty acids via dietary sources are more prone to depression. Some studies have revealed that omega-3 fatty acid supplementation (from fish or algae oil) may help stabilize mood when taken long-term, but the evidence is conflicting. Unlike other dietary supplements, omega-3 fatty acids (fish or algae oil) can be used as adjunctive therapy with prescribed antidepressants such as SSRIs and SNRIs without heightening the risk of dangerous drug interactions or serotonin syndrome. However, it has been known to interact with anticoagulants such as aspirin (ASA) and coumadin (Warfarin) by increasing the risk of bleeding. Furthermore, not all omega-3 fatty acids (fish or algae oil) supplementations are created equal. Without FDA regulation, there is an ongoing concern regarding the purity of ingredients. Toxins and contaminants have been found in some omega-3 fatty acids (fish or algae oil) preparations, such as mercury and dioxins (industrial toxins) found in predatory fish (e.g., salmon, swordfish, perch, pike, and tuna; Cheng et al., 2025; NCCIH, 2021). Additionally, potential adverse effects include the following:

• allergic reactions in patients who have underlying fish allergies
• hyperglycemia
• increased vitamin D and A levels
• may cause increased low-density lipoprotein (LDL) cholesterol levels (Gitlin, 2025; NCCIH, 2021)

S-Adenosyl-L-Methionine (SAM-e)

S-adenosyl-L-methionine (SAM-e) is a naturally occurring chemical component present in all cells of the body, as it serves necessary functions in numerous metabolic pathways. It participates in the synthesis of many essential molecules, including the neurotransmitters norepinephrine, dopamine, and serotonin. SAM-e has been approved for nearly three decades as a prescription drug for depression in several European countries. It may be used alone or as adjunctive therapy with prescription antidepressants, including SSRIs, SNRIs, monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (TCAs). Studies demonstrate that SAM-e poses fewer side effects than prescription antidepressants, with mild nausea reported as the most common side effect. It can worsen underlying agitation, panic, or anxiety in some patients. SAM-e works more rapidly than prescription antidepressants, does not cause weight gain or sexual dysfunction, and has no known drug interactions. There are no clear guidelines as to whether SAM-e is beneficial for depression. However, evidence supporting the use of SAM-e includes a six-week randomized trial that compared add-on SAM-e (800 mg twice per day) with placebo in 73 patients with unipolar major depression who failed treatment with an SSRI or serotonin-norepinephrine reuptake inhibitor. In this trial, remission occurred in more patients who received SAM-e (Cheng et al., 2025; Gitlin, 2025; Limveeraprajak et al., 2024; NCCIH, 2021).

Saffron (Crocus sativus)

Saffron (Crocus sativus) has been investigated as a potential treatment for depression. Evidence from randomized controlled trials and meta-analyses suggests that saffron may influence the activity of neurotransmitters, including serotonin, dopamine, and norepinephrine. Clinical trials and meta-analyses consistently demonstrate that saffron supplementation is more effective than a placebo and is comparable to SSRIs and TCAs in alleviating depressive symptoms in cases of mild to moderate depression. The typical studied dose is 28–30 mg per day of standardized saffron extract for a duration of 6 to 12 weeks. Saffron is generally associated with fewer and milder side effects compared to conventional antidepressants, its most common side effects being headache, nausea, and dizziness. It does not typically cause weight gain or sexual dysfunction. Serious adverse events are rare, and the tolerability of saffron is high. Saffron has been studied both as a stand-alone treatment and as an adjunct therapy alongside prescription antidepressants, with evidence supporting its safety and efficacy in both contexts. However, caution is advised regarding potential drug interactions, and long-term safety data are still limited (Gitlin, 2025; Han et al., 2024; Siddiqui et al., 2022).

Silexan (Lavandula angustifolia)

Silexan is a proprietary oral preparation of lavender oil (Lavandula angustifolia), standardized in 80 mg capsules, developed for the treatment of anxiety and related disorders. Its mechanism of action involves moderate inhibition of voltage-dependent calcium channels and enhancement of neuroplasticity, leading to downstream effects on intracellular signaling pathways that are relevant to mood regulation. Regarding its efficacy for treating depression, randomized controlled trials and meta-analyses demonstrate that Silexan is effective for mild to moderate MDD, as well as for mixed anxiety and depressive disorder (MADD) and depressive symptoms that co-occur with anxiety. Silexan is generally well tolerated, with adverse events limited primarily to mild gastrointestinal symptoms, such as burping. Importantly, it does not cause sedation, sexual dysfunction, weight gain, withdrawal symptoms, or drug interactions. The evidence supports its use as a safe and effective option for managing mild to moderate depression, particularly when anxiety symptoms are present (Dold et al., 2023; Kasper & Eckert, 2024).

Antidepressants

Antidepressant medications are the pharmacological treatment of choice for depression. Medication therapy aims to help reduce or control the symptoms of depression. The bulk of medications currently FDA-approved for treating depression target the three neurotransmitters historically associated with depression: serotonin, norepinephrine, and dopamine. Due to their side effect profiles, most antidepressants need to be initiated at low doses, tapered up slowly, and tapered down before discontinuing. If they are stopped abruptly, withdrawal-like symptoms may occur, including dizziness, headaches, flu-like symptoms (such as tiredness, chills, muscle aches), agitation, irritability, insomnia, nightmares, diarrhea, and nausea. Discontinuation can also lead to the return of depressive symptoms. Regardless of the medication prescribed, patients must be counseled that antidepressants may take at least 2 to 4 weeks to have an effect and 12 weeks to achieve full benefits. Disturbances in sleep, appetite, and concentration often improve before a notable change in mood. While mild-to-moderate depression can often be treated with therapy alone, moderate-to-severe cases of depression often require the addition of medication. Patients of childbearing age should be advised that most antidepressants were previously categorized by the FDA as pregnancy category C (risk cannot be ruled out) except for paroxetine (category D) and bupropion (category B), with slight variations between the medications’ safety for lactating parents (NIMH, 2023b; Rush, 2025a, 2025b; Simon et al., 2024).

In 2004, the FDA required a warning to be printed on the labels of all antidepressant medications regarding the risk of increased suicidality among children and adolescents taking these medications. The warning was expanded in 2007 to include all young adults, especially those under 25, stating that these individuals may experience increased suicidal thoughts or behaviors during the first few weeks of taking an antidepressant. Before starting medication therapy, the individual may have been too paralyzed by depression to make a suicide plan. Therefore, the risk of suicide rises as symptoms begin to improve on antidepressant therapy. An increase in suicidal thoughts has also been documented in patients taking antidepressants for other conditions or indications. As antidepressants became more commonly prescribed for anxiety and other mental health conditions, reports of patients’ suicidal thoughts and actions became more worrisome to clinicians and family members. If a depressed person on antidepressants becomes suicidal, it is always a cause for concern. However, if someone who was not previously depressed and taking antidepressants for another indication becomes suicidal, it raises additional questions about these medications’ safety. Researchers found evidence that individuals taking antidepressant medication may have an even higher risk of suicide than individuals whose depression is improving for other reasons (Hua et al., 2023). The FDA also requires manufacturers of antidepressants to provide a Patient Medication Guide (MedGuide), which is distributed to patients prescribed these medications, advising them on precautions that can reduce the risk of suicide (FDA, 2018). Table 5 lists the points that must be included in the boxed warning.

Table 5

FDA Antidepressants Boxed Warning Points

Antidepressants increase the risk of suicidal thinking and behavior (suicidality) for children and adolescents with MDD and other psychiatric disorders.

Anyone considering using an antidepressant for a child or adolescent for any clinical indication must balance the risk of increased suicidality with the clinical need.

Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.

Families and caregivers should be advised to observe the patient closely and communicate with the prescriber.

A statement must be made regarding whether the prescribed drug is approved for any pediatric indication(s) and, if so, which one(s).

 (FDA, 2018)

 

The current evidence base does not recommend one prescribed agent over another, although SSRIs are typically cited as the safest initial choice that causes the fewest side effects. A systematic review and meta-analysis published by Cipriani and colleagues in 2018 reviewed 522 double-blind, randomized controlled trials involving 116,477 patients diagnosed with MDD and 21 different antidepressants. Unfortunately, this analysis only recorded outcomes at or around 8 weeks, which is a brief period, especially for long-acting medications. The authors noted that 426 of the 522 (81%) reviewed trials were of moderate- or high-risk bias. Despite these limitations, the results demonstrated that all antidepressants were more effective than placebo. Agomelatine (Valdoxan), amitriptyline (Elavil), escitalopram (Lexapro), mirtazapine (Remeron), paroxetine (Paxil), venlafaxine (Effexor), and vortioxetine (Trintellix) were among the most effective, while fluoxetine (Prozac), fluvoxamine (Luvox), reboxetine (Edronax), and trazodone (Desyrel) were among the least effective. Agomelatine (Valdoxan) is a novel antidepressant that acts as a melatonin agonist and serotonin antagonist. It has been marketed in Europe since 2009 and in Australia since 2010 but is not currently approved by the FDA for use in the United States. Reboxetine (Edronax) is a norepinephrine reuptake inhibitor that is not approved for use in the United States. Regarding tolerability, agomelatine (Valdoxan), citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), sertraline (Zoloft), and vortioxetine (Trintellix) had the lowest dropout rates. In contrast, amitriptyline (Elavil), duloxetine (Cymbalta), fluvoxamine (Luvox), reboxetine (Edronax), trazodone (Desyrel), and venlafaxine (Effexor) had the highest dropout rates. Overall, when evaluating effectiveness as well as tolerability, the authors determined that the best options for the treatment of depression are agomelatine (Valdoxan) and escitalopram (Lexapro) and the worst choices fluvoxamine (Luvox), reboxetine (Edronax), and trazodone (Desyrel; Cipriani et al., 2018; Kishi et al., 2023).

The American Geriatrics Society (AGS) Beers Criteria for Potentially Inappropriate Medication Use in Older Adults (BC) was most recently updated in 2023, replacing the 2019 version. The 2023 AGS Beers Criteria continues to recommend avoiding TCAs in older adults due to their strong anticholinergic properties, which can lead to an increased risk of orthostatic hypotension, sedation, and falls. The criteria also advise against the use of SSRIs and SNRIs in older adults who have a history of falls or fractures unless no safer alternatives are available. This recommendation is based on the well-documented association between these medications and an increased risk of falls. Importantly, the updated guidance emphasizes that there is no substantial evidence indicating that any specific antidepressant has a lower risk of falls compared to others. Recent observational and meta-analytic studies further support this position, showing that SSRIs and SNRIs are associated with roughly a 30% increased risk of falls in older adults, even after accounting for the severity of depression and the presence of other medications (AGS, 2023; Haddad et al., 2021, 2022).

While antidepressants typically do not require routine laboratory or drug-level monitoring, nurses should remain alert to the potential side effects and adverse effects outlined in each of the following categories. APRNs should counsel patients that side effects typically improve after the first 2 weeks of treatment. As a drug class, the most common adverse effects of antidepressants include nausea, weight gain, diarrhea, sleepiness, and sexual dysfunction (i.e., loss of libido or impotence (Coryell, 2023; Rush, 2025b). The major antidepressant drug classes are outlined in the next section and Table 6.

SSRIs and SNRIs

SSRIs work by selectively blocking the serotonin transporter (SERT), which increases the concentration of extracellular serotonin in the central nervous system. This mechanism is thought to be responsible for their antidepressant effects. Commonly prescribed SSRIs include citalopram (Lexapro), escitalopram (Citalopram), fluoxetine (Prozac), fluvoxamine (Fluvox), paroxetine (Paxil), sertraline (Zoloft), and vortioxetine (Trintellix). Although vortioxetine is classified as an SSRI, it has additional multimodal serotonergic properties (Coryell, 2023; Rush, 2025b).

In terms of pediatric use, fluoxetine is the only SSRI approved by the FDA for treating MDD in children aged 8 and older, while escitalopram is approved for adolescents aged 12 to 17 years. Other SSRIs may be used off-label in pediatric populations (Strawn et al., 2023).

Common side effects of SSRIs can include gastrointestinal symptoms (such as nausea, vomiting, and diarrhea), headaches, dry mouth, sedation or insomnia, nervousness, agitation, restlessness, sexual dysfunction, and changes in appetite and weight. Some rarer but clinically significant adverse effects include hyponatremia (often linked to syndrome of inappropriate antidiuretic hormone secretion [SIADH]), abnormal bleeding—especially when taken alongside NSAIDs, antiplatelet medications, or anticoagulants (Coryell, 2023; Pinkhasov et al., 2021; Rush, 2025b).

SNRIs include duloxetine (Cymbalta), venlafaxine (Effexor), desvenlafaxine (Pristiq), and levomilnacipran (Fetzima). Side effects include nausea, headaches, dizziness, excessive sweating, dry mouth, tiredness, constipation, insomnia, sexual dysfunction, and anorexia. Patients prescribed venlafaxine (Effexor) should have their blood pressure checked at baseline and periodically after starting and following any dose increase to monitor for hypertension (Rush, 2025b; Woods, 2023).

SSRIs and SNRIs can increase serotonin levels in the body, posing a risk of serotonin syndrome. Serotonin syndrome is characterized by agitation, anxiety, confusion, a high fever, sweating, tremors, a lack of coordination, dangerous fluctuations in blood pressure, and rapid heart rate. Patients must seek immediate medical attention because this is a potentially life-threatening condition. Furthermore, SSRIs and SNRIs are associated with increased suicide risk and withdrawal symptoms if stopped abruptly. These medications should not be used within 14 days of an MAOI (Rush, 2025b; Woods, 2023).

Tricyclic Antidepressants and Tetracyclic Antidepressants

TCAs and tetracyclic antidepressants are an older class of medications that include nortriptyline (Pamelor), imipramine (Tofranil), amitriptyline (Elavil), and desipramine (Norpramin). TCAs inhibit norepinephrine and serotonin reuptake but with significantly more adverse effects, such as sedation, increased appetite, weight gain, dry mouth, constipation, hypotension, lightheadedness, drowsiness, blurred vision, tremors, excessive sweating, and sexual dysfunction. Less common but serious side effects include life-threatening irregular heart rate, urinary retention, and seizures. Before being prescribed TCAs, patients should be evaluated for the presence of any cardiac history, and a baseline electrocardiogram (ECG) should be performed. TCAs also carry a risk of serotonin syndrome, suicide, and withdrawal symptoms if discontinued abruptly. These medications should also be avoided within 14 days of MAOI use (Coryell, 2023; Rush, 2025b; Woods, 2023).

Mirtazapine (Remeron) is an atypical tetracyclic antidepressant that antagonizes alpha-2 adrenergic and serotonin receptors. It can cause increased cholesterol and triglyceride levels and should be used cautiously by patients with a personal or family history of heart disease or irregular heart rhythm. Mirtazapine (Remeron) should not be taken within 14 days of an MAOI due to the heightened risk for serotonin syndrome. Other common side effects include sedation, increased appetite, weight gain, and dizziness. Rare and serious side effects consist of agranulocytosis (low white blood cells) and angle-closure glaucoma (eye pain, changes in vision, swelling, or redness in or around the eye). Nurses should advise patients to take the medication before bedtime to avoid daytime drowsiness, especially if performing tasks that involve alertness, such as operating heavy machinery (Coryell, 2023; Rush, 2025b; Woods, 2023).

Monoamine Oxidase Inhibitors

MAOIs were the first type of antidepressant developed. They impair the metabolism of serotonin and block MAOI, an enzyme that breaks down excess tyramine in the body. Tyramine is an amino acid that helps regulate blood pressure and is found naturally in the body and in certain foods. MAOIs include tranylcypromine (Parnate), phenelzine (Nardil), isocarboxazid (Marplan), and a transdermal skin patch selegiline (Emsam). Due to the risk of serious adverse effects, the use of MAOIs for the treatment of depression is reserved for patients who have failed all other treatment options. MAOIs have dangerous drug and food interactions; nurses must warn patients to avoid foods containing high levels of tyramine, such as aged cheese (aged cheddar, swiss, parmesan, and blue cheeses); cured, smoked, or processed meats (pepperoni, salami, hotdogs, bologna, bacon, corned beef, smoked fish); pickled or fermented foods (sauerkraut, kimchi, tofu); sauces (soy sauce, miso and teriyaki sauce); soybean products; and alcoholic beverages (beer, red wine, liquors). Other side effects of MAOIs include dry mouth, nausea, diarrhea or constipation, headaches, drowsiness, insomnia, dizziness, lightheadedness, hypotension, loss of libido, weight gain, urinary retention, involuntary muscle jerks, muscle cramps, and paresthesia. MAOIs are associated with increased suicidality and withdrawal symptoms if stopped abruptly. Patients should also be counseled to avoid OTC decongestants and other cold medications due to the heightened risk for dangerous hypertensive crises (Sub Laban & Saadabadi, 2023; Woods, 2023).

Table 6

Antidepressants by Medication Class

   

Drug Class

SSRIs

Drug

Citalopram (Celexa)

Escitalopram (Lexapro)

Fluoxetine (Prozac)

Paroxetine (Paxil)

Sertraline (Zoloft)

Vortioxetine (Trintellix)

Patient Education

Continue therapy even after symptoms improve Avoid alcohol Females of reproductive age must use contraception Be cautious when operating heavy machinery

Drug Class

SNRIs

Drug

Duloxetine (Cymbalta)

Venlafaxine (Effexor)

Desvenlafaxine (Pristiq)

Levomilnacipran (Fetzima)

Patient Education

Do not stop therapy abruptly Avoid activities that are hazardous or that require mental alertness Avoid alcohol consumption Sexual dysfunction may occur

Drug Class

TCAs and Tetracyclic Antidepressants

Drug

Amitriptyline (Elavil)

Nortriptyline (Pamelor)

Imipramine (Tofranil)

Desipramine (Norpramin)

Mirtazapine (Remeron)

Patient Education

For higher doses, administer in the late afternoon or evening to prevent daytime sedation When taken at bedtime, morning orthostatic hypotension may occur; change positions slowly when getting out of bed Avoid activities that require alertness or psychomotor coordination Can combat dry mouth by sucking on hard candies or chewing gum

Drug Class

MAOIs

Drug

Tranylcypromine (Parnate)

Phenelzine (Nardil)

Isocarboxazid (Marplan)

Selegiline (Emsam)

Patient Education

Selegiline (Emsam) use may result in a positive urine test for amphetamines apply the patch to dry, intact skin on the upper torso, thigh, or outer arm every 24 hours apply the patch at the same time every day do not cut the patch into smaller pieces Avoid alcohol consumption Avoid all foods containing tyramine Avoid cold and flu medications

(Woods, 2023)

Uncategorized and Atypical Antidepressants

There are a few uncategorized and atypical antidepressants that have varying mechanisms of action. Bupropion (Wellbutrin) is an atypical antidepressant that works by inhibiting the reuptake of dopamine, serotonin, and norepinephrine. It is prescribed for depression, as well as SAD and smoking cessation. Bupropion (Wellbutrin) is one of the few antidepressants not frequently associated with sexual dysfunction. However, it poses a seizure risk, so it should be avoided in patients with preexisting seizure disorders. It primarily affects dopamine in the brain and therefore does not carry a risk of serotonin syndrome. The most common side effects include headaches, weight loss, dry mouth, insomnia, nausea, dizziness, constipation, fast heartbeat, and sore throat (Coryell, 2023; FDA, 2017; Rush, 2025b; Woods, 2023).

Dextromethorphan-bupropion (Auvelity) is an antidepressant that combines dextromethorphan, an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, with bupropion, a norepinephrine-dopamine reuptake inhibitor (NDRI). The bupropion component also functions as a CYP2D6 inhibitor, prolonging dextromethorphan’s half-life and enhancing its clinical activity. Auvelity (dextromethorphan-bupropion) is FDA-approved for the treatment of MDD in adults. MAOIs should be discontinued at least 14 days before initiating Auvelity (dextromethorphan-bupropion). Adverse effects commonly include dizziness, headache, somnolence, dry mouth, constipation, and increased blood pressure. Patients should be monitored for neuropsychiatric effects such as agitation, mania, or worsening depression and suicidality. As with other bupropion-containing products, Auvelity (dextromethorphan-bupropion) carries a dose-related risk of seizures. Auvelity (dextromethorphan-bupropion) has a faster onset of antidepressant effect compared to traditional SSRIs/SNRIs, with some patients experiencing symptom improvement within 1–2 weeks. Patients should avoid alcohol consumption while on this medication due to potential neuropsychiatric effects and increased seizure risk (Thase & Connolly, 2023; Willett et al., 2024).

Trazodone (Desyrel) is an antidepressant that inhibits both serotonin transporters and serotonin type 2 receptors. It inhibits the reuptake of serotonin and blocks histamine and alpha-1-adrenergic receptors. It is usually prescribed for depression when other medications have failed. Nurses must ensure that MAOIs were discontinued at least 14 days before administering trazodone (Desyrel). Patients should be advised to take the medication before bedtime due to drowsiness and sedation. Rare adverse effects include priapism (a persistent and painful erection not associated with sexual arousal) and cardiac arrhythmias (Coryell, 2023; Shin & Saadabadi, 2024; Rush, 2025b).

Zuranolone (Zurzuvae) is an oral neuroactive steroid and GABA-A receptor positive allosteric modulator approved for the treatment of depression with peripartum onset. It is administered as a 14-day course and represents a new class of rapid-acting antidepressants (Gitlin, 2025; Gonda et al., 2023).

Gepirone (Exxua) is a 5-HT1A receptor partial agonist approved for the treatment of MDD in adults. It is associated with a favorable side effect profile, particularly low rates of sexual dysfunction, weight gain, and sedation (Drugs.com, 2025).

Resistant Depression

Depression may be resistant to standard treatments, with up to 67% of patients failing to respond to first-line therapy. Resistant depression is the failure of at least two other antidepressants (administered for at least 6 weeks each) without achieving remission or at least a 50% improvement in mood. Often, the resistance is not related to the medication or treatment but to adherence with administration by the patient. Lack of response can also be due to an incorrect dose or inadequate time to develop a therapeutic response. For some patients, a change in medication therapy may be warranted, such as switching from an SSRI to an SNRI or adding a second medication to the regimen. Psychotherapy should be added if not already a component of the treatment plan, and brain-stimulation therapies can be considered (APA, 2022; Chen et al., 2025; Thase & Connolly, 2023)

Esketamine (Spravato)

Esketamine (Spravato) is an NMDA antagonist made from ketamine, an anesthetic introduced in the 1960s to treat battle wounds during the Vietnam War. Since then, ketamine has gained attention regarding its role in treating severe depression. In 2019, esketamine (Spravato) nasal spray, a more potent version of ketamine, earned FDA approval when used in conjunction with an oral antidepressant for adults with treatment-resistant depression. Esketamine (Spravato) works by increasing levels of the neurotransmitter glutamate in the brain. It has a rapid onset, immediately impacting brain cells and offering relief from depressive symptoms within hours. Common side effects include dissociation (e.g., difficulty with attention, judgment, and thinking), nausea, dizziness, drowsiness, vertigo, and anxiety. It has a boxed warning related to its risk of sedation, dissociation, misuse, dependence, and suicidal thoughts and behaviors. Therefore, it is a federally controlled substance only available through a Risk Evaluation and Mitigation Strategy (REMS) program. Esketamine (Spravato) must be administered under the supervision of an HCP in a health care setting that is certified in the REMS program. Patients cannot take the spray home and must be monitored for signs of sedation and dissociation for at least 2 hours following each dose. During the first 1 to 4 weeks of treatment, administration is twice weekly. It is then administered once weekly during weeks 5 to 8. The recommended maintenance dose is either once weekly or every other week, depending on the patient’s response (FDA, 2019; Coryell, 2023; NIMH, 2023b; Thase & Connolly, 2023; Woods, 2023).

Brain Stimulation Therapy

Brain stimulation therapies are typically reserved for treating resistant depression when other treatments have proven ineffective. The three major types consist of ECT, repetitive transcranial magnetic stimulation (TMS), and vagus nerve stimulation (Chen et al., 2025; National Alliance on Mental Illness [NAMI], n.d.).

Electroconvulsive Therapy

ECT involves transmitting short electrical impulses into the brain. These controlled electrical currents provoke a brief period of seizure-like activity. ECT is typically performed in a series of 4 to 6 treatments before an improvement can be expected, with a total of 6 to 12 treatments administered over 2 to 6 weeks; monthly maintenance treatments are sometimes required. The patient is placed under general anesthesia for the treatments and can resume regular activity about an hour following the procedure. ECT can have significant adverse effects, such as headaches, muscle pain, nausea, confusion, and memory loss. It is utilized only for patients with severe depression, depression with psychosis, or bipolar disorder that has not responded to medication and psychotherapy with more conventional methods. In uncomplicated severe depression, ECT has been shown to improve mood in 80% of patients. Patients need to understand the potential risks and benefits of ECT before beginning treatment. ECT remains the most effective intervention for severe MDEs, including those with psychotic features, catatonia, and bipolar depression refractory to medication. It is indicated for patients with treatment-resistant depression (failure of at least two adequate antidepressant trials), severe suicidality, psychosis, or when a rapid response is required. ECT is also used in bipolar mania and mixed states and has demonstrated efficacy in treatment-resistant schizophrenia, although its use in obsessive-compulsive disorder (OCD) is not supported by robust evidence (Espinoza & Kellner, 2022; Holtzheimer & Phillip, 2025; NAMI, n.d.; Thase & Connolly, 2023).

Transcranial Magnetic Stimulation

TMS is a type of brain stimulation that uses a magnet instead of an electrical current to activate the brain. TMS, particularly repetitive TMS (rTMS), is FDA-approved for treatment-resistant MDD and OCD. It is less invasive than ECT, does not require anesthesia, and is associated with minimal cognitive side effects. Efficacy is established for unipolar and likely bipolar depression, with remission rates lower than ECT, especially in psychotic depression. TMS is well tolerated. Patients may need to complete 4 to 5 sessions lasting 40 minutes each per week over 4 to 6 weeks to notice improvement. The patient remains alert throughout the treatment, and general anesthesia is not required. Mild adverse effects include muscle contractions, facial and jaw tingling, headaches, and lightheadedness (Chen et al., 2025; Holtzheimer & Phillip, 2025; NAMI, n.d.; Thase & Connolly, 2023).

Vagus Nerve Stimulation

VNS is FDA-approved for resistant depression only after attempts with four different medications and ECT have failed. Originally developed to treat seizure disorders, its use in depression treatment is controversial and rare. VNS requires the placement of a pulse stimulator on the upper left chest to stimulate the vagus nerve. The VNS sends an electrical pulse up the vagus nerve to the brainstem to change the function of brain cells. How it functions can be compared to a pacemaker’s effect on cardiac cells. Adverse effects include voice changes, hoarseness, a sore throat, coughing, difficulty swallowing, neck pain, and breathing difficulty while exercising (Holtzheimer & Phillip, 2025; NAMI, n.d.).

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