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Fundamentals of Major Depressive Disorder

Major depressive disorder (MDD) is one of the most recognized mental disorders in the US. Learn more about the prevalence, pathophysiology, diagnosis, and management of MDD here.

Patients with major depressive disorder experience episodes of sadness or feelings of worthlessness that can make routine tasks such as working,1,2 caring for others, 3,4 sleeping,5 eating well,6-8 and exercising 9,10 seem insurmountable. Proper care, including pharmacotherapy,11 psychotherapy,12,13 and the support of family and friends,14-16 creates a recovery support system, helping individuals become more resilient and live independent fulfilling lives once again.17-19

Introduction to Major Depressive Disorder

What is major depressive disorder?

There is a lot of stigma surrounding depressive disorders, making it difficult for patients to be open about their diagnosis and seek treatment. Understanding their depressive symptoms and options for management can help provide hope to patients. Depressive disorders are typically characterized by feelings of sadness, depression, or irritability.20 While the various depressive disorders share common symptoms, the specific types are differentiated by the timing and length of the symptoms.20 Major depressive disorder is the most recognized disorder in this group. People with major depressive disorder experience prolonged depressive episodes that involve changes in mood, cognition, and a loss of interest and pleasure in previously-enjoyed activities.20 

Types of depressive disorders

The DSM-5 (2013) describes 3 depressive disorders that affect adults.

Major depressive disorder

Characterized by a depressed mood for at least 2 weeks20

Persistent depressive disorder

Characterized by a depressed mood for most days for 2 years20

Premenstrual dysphoric disorder

Marked depressed mood or irritability develop during the week before menses. These symptoms are minimal or absent once monthly menses is complete20

Depressive disorders may be secondary to another process or may present differently than the types listed above.

  • The use of mind-altering substances, some medications, and some medical conditions can cause depressive-like symptoms. In these cases, a diagnosis of substance/medication-induced depressive disorder or depressive disorder due to another medical condition may be given.20
  • A patient with depressive symptoms that do not fit the criteria for any of the above disorders may be classified as having other specified depressive disorder.20 
  • Sometimes when no specific diagnosis can be made, such as in an emergency department in which pertinent medical information is unavailable, a diagnosis of unspecified depressive disorder may be rendered.20

What is the burden of major depressive disorder?


Depressive disorders are the leading cause of disability in adults worldwide.21

In the U.S., 18.3% of adults aged 18–64 years will be given a diagnosis of major depressive disorder at some point in their lifetime. Females are more likely than males to develop the disorder. In 2017, 1,090,070 people in the U.S. received a depressive disorder diagnosis and 17.3 million adults had at least one major depressive episode. References 22, 23, 24 and 25]

Functional impairment

Major depressive disorder can reduce your patients’ quality of life and may make performing day-to-day functions difficult.26 Depressive episodes can affect memory, attention span, conversational skills, and executive functioning, which involves decision making and task completion.23,26,27 These difficulties can persist outside depressive episodes.23,26 Research has shown that higher levels of education can confer protection against depressive symptoms.28

Relationships with coworkers, friends, and acquaintances may also be affected by depressive symptoms. People with major depressive disorder can miss work due to their illness and, when at work, may perform responsibilities poorly or ineffectively due to their condition.26 In a survey from 2001–2003, people with major depressive disorder lost an average of 27.2 workdays—8.7 days were due to absenteeism and 18.2 days from presenteeism.29 Problems with memory, attention, and executive function are also associated with lower wages and unemployment.26,28 Patients with major depressive disorder may have difficulty extricating themselves from their own thoughts and, as a result, may appear self-focused and disinterested in social activities and forging bonds with others.30 Along with a diminished ability to read nonverbal cues from other people, they may come across as insensitive and have few friends.30 

Caregivers such as family and friends of people with major depressive disorder can also be negatively impacted. This unpaid informal work can be time consuming and emotionally challenging31, possibly leading to lost income and health insurance due to reduced work hours.32 In addition, they may experience fatigue, distress, and poor sleep, and may develop depressive symptoms themselves.32 


People with major depressive disorder are at an increased risk for developing cardiovascular disease, diabetes mellitus, obesity, metabolic syndrome, epilepsy, stroke, Alzheimer’s disease, and cancer.23,33 Some of these conditions, such as obesity34 and cardiovascular disease,35,36 have also been linked to the development of major depressive disorder. Insomnia is also associated with an increased risk for developing major depressive disorder.37 Comorbidities can make it more difficult to adequately treat major depressive disorder and can increase cognitive dysfunction.23,38

Suicide Risk

Suicide is a significant concern; people with major depressive disorder have an almost 20-times greater risk of attempting suicide than the general population, more than half will have suicidal ideation at least once in their lifetime, and 31% will attempt suicide.23,39,40  

A U.S. survey from 2012–2013 found that 305 adults (of more than 30,000 surveyed) had attempted suicide in the last 3 years. Of those who attempted suicide, 54% had major depressive disorder in the year prior to the survey.41 The presence of mixed features (manic symptoms) during a depressive episode increases the risk of suicide.42 Because of the high risk of suicide, screening your patients regularly for suicidal thoughts or intent is important. See ‘Diagnosis’ below for more information on screening and assessment.

Pathophysiology of Major Depressive Disorder

What do we know about the causes?

Misperceptions about major depressive disorder persist despite the body of research suggesting the disorder is as real and concrete as the common cold.43,44 This lingering stigma may lead some patients and their families to underestimate the severity or significance of major depressive disorder symptoms.45,46 Instead, they may blame external causes such as stress or relationship problems rather than considering biologically based factors.47,48 Such misunderstanding can hinder recovery by inadvertently causing delays in seeking treatment for symptoms45 , and when these patients do reach out, they may not adhere to treatment as prescribed or recommended.43,49 When you educate your patients about major depressive disorder being a medical condition that has biological and environmental causes, you can empower them to become an active part of their treatment plan and recovery.43 Scroll down to the Treatment Guidelines and Non-Pharmacological Management sections for more details on treatment plans.


Although researchers have not found any single mechanism known to cause major depressive disorder, they are aware that it may have a genetic component.23,50-57 Genetics cause 28–44% of the variation observed in how major depressive disorder presents.50,52,54 First-degree relatives of people who have major depressive disorder have an almost 3-fold risk of developing it.57 Many genes contribute to the condition, including some related to neuroticism, which has been linked in the development of major depressive disorder.51,53,55,56 Identifying candidate genes is difficult, because many are likely to confer higher risk only when combined with specific environmental stressors.23


Multiple neurobiological processes are thought to contribute to major depressive disorder. The brains of people who have this condition have been shown to have lower cortical thickness and cell density in the prefrontal cortex, reduced hippocampus volume, and changes to synapse structure and function.58

Several biomarkers have been identified as related to synapse function.58 Two of these biomarkers, brain-derived neurotrophic factor and protein p11, have been identified as potential biomarkers for predicting antidepressant response and risk of suicidality, respectively.58 Epigenetics are also thought to play a role in synapse plasticity.58 Antidepressants, exercise, and electroconvulsive therapy have been shown to promote increased hippocampus volume and neuroplasticity.59,60


Stressful events, including job strain, loss of employment, financial insecurity, health problems, exposure to violence, separation from a partner or family, and grieving the loss of a loved one, can initiate a depressive episode.61-64

Increased levels of cortisol, a glucocorticoid hormone associated with acute and chronic stress, are a risk factor for major depressive disorder.65-67 Using synthetic glucocorticoids for the management of other medical disorders, such as autoimmune diseases and asthma, can increase the risk of major depressive disorder and suicide.68,69 For some people who have major depressive disorder, an overactive peripheral immune system can lead to high levels of proinflammatory cytokines.58 Some research shows that maternal stress in utero may be connected with the development of depressive symptoms when the children become adolescents.70,71 The stress of pregnancy and birth leads to major depressive disorder for 6–8% of women annually in the U.S.72

Prevention and future research

While some causes cannot be avoided, there are steps that can be taken to reduce the risk for developing major depressive disorder. Prevention tactics can include the patient learning how to strengthen social networks and problem-solving skills, and proactively treating depressive symptoms before they develop into major depressive disorder. 

Taking these steps and others can lead to an average of a 21% reduction in the incidence of major depressive disorder.73 For people with high inflammatory biomarkers, treating the inflammation can also treat depressive symptoms.74,75 Current research includes identification of biomarkers to help predict response to treatment, development of more rapid-acting pharmacological treatments, and enhancement of brain stimulation techniques as treatment options.76


An accurate diagnosis is important for delivering the best quality of care. However, depressive disorders can be difficult to diagnose.77 Age, living in a rural setting, and somatic symptoms are a few factors that can contribute to a delayed diagnosis or misdiagnosis.77,78 You and your colleagues play an important role in diagnosing and managing patient treatment, especially in a general practice setting.79

The DSM-5 (2013) describes 3 depressive disorders that affect adults.

Major depressive disorder

Characterized by a depressed mood for at least 2 weeks. A depressed mood can include decreases in energy, changes in sleep patterns, and feelings of worthlessness or guilt. Other symptoms may include a loss of pleasure or interest in daily activities, frequent hypersomnia or insomnia, fatigue, and difficulty concentrating.20  

Persistent depressive disorder

Characterized by a depressed mood for most days for 2 years. A depressed mood can include decreases in energy, changes in sleep patterns, and feelings of worthlessness or guilt. Other symptoms may include hypersomnia or insomnia, fatigue, low self-esteem, and difficulty concentrating.20 

Premenstrual dysphoric disorder

Significant or sudden mood swings, irritability or anger, depressed mood, lethargy, and loss of pleasure or interest in daily activities develop during the week before menses. These symptoms are minimal or absent once monthly menses is complete.20 

Depressive symptoms may be secondary to another process or may present differently than the depressive disorders listed above.

  • The use of mind-altering substances, some medications, and some medical conditions can cause depressive-like symptoms. In these cases, a diagnosis of substance/medication-induced depressive disorder or depressive disorder due to another medical condition may be given.20 
  • Depressive symptoms that do not fit the criteria for any of the above disorders may be classified as other specified depressive disorder.20 Sometimes, when no specific diagnosis can be made such as in an emergency department in which pertinent medical information is unavailable, a diagnosis of unspecified depressive disorder may be rendered.20

When considering a depressive disorder diagnosis for your patients, rule out other causes of the presenting symptoms, such as medication or another medical condition. See the end of the Diagnosis section for examples of conditions that can cause depressive-like symptoms.

Signs and symptoms

Talking to your patients

While one of the more common mental disorders, depressive disorders can still be difficult to diagnose. General practitioners misdiagnose depressive disorders, either through a mistaken diagnosis or a missed diagnosis, approximately 25% of the time.80

In large part, this is likely due to how difficult it can be to identify symptoms that are not severe or acute.80 Current diagnostic tools also do not always prioritize those depressive symptoms that are most associated with the correct diagnosis of depressive disorders.81,82

Another part of making an accurate diagnosis is asking the right questions. Patients with bipolar disorder often get misdiagnosed with major depressive disorder.83 For example, in one large study, 31.2% of patients that screened positive for bipolar disorder had previously received a diagnosis of unipolar depression.84 One reason this happens is because patients may not report hypomanic symptoms, as they do not perceive them to be a problem85, or they do not think of them as connected to a mental disorder.86,87 For other examples of disorders that may have similar symptoms to depressive disorders, scroll down to “Differential diagnoses to consider” at the end of this section. 

It can be difficult to translate a list of discrete, clinical symptoms to a diagnosis. When assessing a patient, ask about specific symptoms in a way that is approachable. Some ways to do this are:

  •  Describe symptoms in a way that your patients can relate to in their day-to-day lives. Encouraging detailed responses and being sensitive to different interpretations of severity of symptoms may help with your patients’ understanding and lead to a more complete understanding of symptoms.88,89
  • Collect a thorough history, including asking about symptoms of hypomanic, manic, or depressive episodes in close family members to rule out bipolar depression.85 Try to get your patient to think about symptoms that may have happened further back than the last few months.
  • Developing a strong relationship with your patient may help to lessen the stigma of a mental disorder diagnosis.90,91 It can also help reduce stress, encourage patients to be involved with their care plan and help increase treatment adherence.91
  • Avoid using jargon—using plain language and avoiding technical medical terms will improve your communication with your patient.92 Additionally, using proper terminology may help to lessen the stigma of a mental disorder diagnosis.93,94

Using these methods to communicate the symptoms listed here can be helpful for patient communication and making a diagnosis.

Major depressive disorder20 

For a diagnosis of major depressive disorder, at least five symptoms must be present most days for 2 weeks or more and one of the symptoms must be depressed mood or loss of interest or pleasure in usually enjoyed activities (both symptoms may be present). This mood is accompanied by several additional symptomsa :

  • Decrease or increase in appetite, or a ≥5% unintentional increase or decrease in weight over a month
  • Insomnia or hypersomnia
  • Psychomotor agitation or retardation observable by others
  • Fatigue or loss of energy
  • Feelings of worthlessness, or excessive or inappropriate guilt
  • Inability to think, concentrate, or make decisions
  • Recurrent thoughts of death, recurrent suicidal ideation, having a specific plan for suicide, or a suicide attempt

Other symptomsa that are associated with major depressive disorder, but cannot be used exclusively for a diagnosis, include20:

  • Tearfulness
  • Irritability
  • Brooding and obsessive rumination
  • Anxiety, including excessive worry over physical health
  • Phobias
  • Pain such as back pain, chest pain, or headaches95
  • Nausea95 
  • Labored breathing95
  • Heart palpitations95
  • Diarrhea95
  • Heavy limbs or a feeling of heavy paralysis96
  • Lack of motivation96
  • Apathy96
  • Decreased muscle strength96
  • Difficulty remembering words or events96
  • Difficulty maintaining mental focus96
  • Sexual dysfunction, including decreased libido and sexual desire, as well as problems with arousal and orgasm97

Persistent depressive disorder (dysthymia)20 

For a diagnosis of persistent depressive disorder, or dysthymia, a person has a depressed mood most days for 2 years or more. This mood must be accompanied by at least two additional symptomsa

  • Poor appetite or overeating
  • Insomnia or hypersomnia
  • Fatigue or loss of energy
  • Inability to think, concentrate, or make decisions
  • Feelings of hopelessness

Other symptoms that are associated with major depressive disorder, but cannot be used exclusively for a diagnosis, include:98

  • General feeling of being unwell 
  • Gloominess 
  • Pessimism, sarcasm, or nihilism 
  • A feeling of chronic fatigue 
  • Low self-confidence 

It is possible for a person to have persistent depressive disorder with periods of major depressive disorder.

Premenstrual dysphoric disorder20

Symptomsa are present in the week prior to the majority of menses cycles and improve within a few days of the onset of the menses cycle. These symptoms are minimal or absent once the menses cycle is complete. 

At least one symptom from each list must be present, and at least five symptoms total must be present for a diagnosis.

At least one of these symptoms must be present:

  • Marked affective lability
  • Marked irritability, anger, or increased conflicts
  • Marked depression, feelings of hopelessness, or self-deprecating thoughts
  • Marked anxiety and/or tension

At least one of these symptoms must also be present:

  • Decreased interest in activities
  • Difficulty concentrating
  • Fatigue, lethargy, or lack of energy
  • Marked change in appetite, overeating, or specific food cravings
  • Hypersomnia or insomnia
  • Feeling overwhelmed or out of control
  • Physical symptoms (breast tenderness or swelling, joint or muscle pain, feeling bloated, weight gain)

Other symptomsa that are associated with premenstrual dysphoric disorder, but cannot be used exclusively for a diagnosis, include:

  • Delusions or hallucinations20
  • Thoughts of suicide, suicidal ideation, plans for suicide, or suicide attempt20,99
  • Self-doubt100
  • Difficulty with social interactions100,101
  • Guilt or overcompensation related to presenteeism100
  • Impulsivity101


Specifiers are descriptors in the DSM-5 that can be added to a diagnosis of major depressive disorder or persistent depressive disorder, allowing for the description of additional symptomsa or patterns that are not part of the base diagnosis.20 A patient who has a specifier as a part of their diagnosis is not unusual – rather, the specifiers allow for a more nuanced diagnosis and treatment plan.


Can be applied to…
Anxious distress
The presence of at least two of the following symptoms for most days: 
  • Feeling keyed up or tense
  • Feeling unusually restless
  • Trouble concentrating because of worry
  • Fearing that something awful may happen
  • Feeling that the individual will lose self-control 
The most recent or current major depressive episode or persistent depressive disorder
Atypical features
The presence of mood reactivity, when the mood brightens in response to actual or potential positive events, along with at least two of the following symptoms: 
  • Significant increase in appetite or weight gain
  • Hypersomnia
  • Leaden paralysis
  • Pattern of rejection sensitivity that is present regardless of mood state
The most recent or current major depressive episode or persistent depressive disorder
  • Catatonia20 
Three or more of the following symptoms are present for most of the episode:
  • Stupor, or lack of psychomotor activity
  • Catalepsy, or being able to be passively put in and then holding a posture against gravity
  • Waxy flexibility, or little resistance to being positioned
  • Posturing, or setting and actively maintaining a posture against gravity
  • Mutism, or little to no verbal response
  • Negativism, no response or opposition to instructions or external stimuli
  • Mannerism, or exhibiting caricatures of normal actions
  • Agitation that is not a reaction to external stimuli
  • Grimacing, or inappropriate facial expressions
  • Echolalia, or mimicking the speech of another
  • Echopraxia, or mimicking the movement of another 
The most recent or current major depressive episode or persistent depressive disorder
Melancholic features
A loss of pleasure in most activities or experiencing few or no feelings of pleasure when something good happens, along with at least three of the following symptoms:
  • Depressed mood with profound despondency, despair, or moroseness
  • Depression that is worse in the morning
  • Early-morning awakening
  • Psychomotor agitation or retardation
  • Anorexia or significant weight loss
  • Excessive or inappropriate guilt
The most severe stage of a current major depressive episode or persistent depressive disorder
Mixed features
At least three of the following hypomanic or manic symptoms are present: 
  • Elevated or expansive mood 
  • Inflated self-esteem or grandiosity
  • More talkative than usual
  • Racing thoughts
  • Increase in energy or goal-directed activity
  •  Involvement in activities that have a high potential for painful consequences
  • Decreased need for sleep
The most recent or current major depressive disorder episode 
Peripartum onset
The onset of the depressive episode happens during pregnancy or in the 4 weeks postpartum.
The most recent or current major depressive episode 
Psychotic features
The presence of delusions or hallucinations during an episode.
The most recent or current major depressive episode or persistent depressive disorder
Seasonal pattern
A long-term pattern of depressive episodes that occur and then subside corresponding with a particular time of year. This must happen for at least 2 years, with no nonseasonal episodes occurring during that same period.
Recurrent major depressive disorder episodes

 aThe symptoms in these definitions are adapted from the DSM-5 (2013) so as to avoid any misinterpretation. Please refer to the DSM-5 (2013) published by the American Psychiatric Association for the full diagnostic criteria.

Diagnostic and screening tools

You can use a number of validated scales to assess symptoms related to depressive disorders. While these scales are useful tools, depressive disorders have many types of symptoms. making it important to carefully assess the whole patient prior to making a diagnosis.102,103 A selection of a diagnostic and screening tools can be found here. For additional information about the diagnosis process, scroll down to the Treatment Guidelines section.

Differential diagnosis to consider

Depressive disorders have symptoms that overlap with other mental disorders, which can make them difficult to diagnose.20 A careful evaluation of patient symptoms and history is important for proper treatment. The following lists are differential diagnoses that should be considered prior to making a diagnosis of a depressive disorder.

Other diagnoses that should be considered prior to making a diagnosis of major depressive disorder or persistent depressive disorder include:

Other depressive disorders

Differential diagnoses are made by a careful consideration of the timing and length of the symptoms.20

Depression due to substance use, a medical condition, or medication

Careful examination of patient history, laboratory results and the timing of depressive symptoms in relation to the use of substances or medication can help make an accurate diagnosis.20

Bipolar disorder

If a person has experienced at least one episode of mania or hypomania at any point in their life, a diagnosis of a depressive disorder is excluded.23 However, mixed symptoms in depressive disorders are a risk factor for the development of bipolar disorder, and patients with this specifier should be monitored for a hypomanic or manic episodes.20


Depressive symptoms are a common associated feature of chronic psychotic disorders.23 Identifying the timing of delusions in relationship to mood disorders can aid diagnosis: if delusions only occur during depressive episodes, the diagnosis is more suggestive of depression with psychotic features.20

Personality disorder

Personality disorders share many characteristics with other mental disorders. A personality disorder should be diagnosed only when the defining characteristics have been present since before early adulthood and are typical of the patient’s long-term behavior. Personality disorders are also persistent and do not occur in an episodic manner.20 

Significant loss

Losses such as bereavement, a serious illness, natural disasters, or financial distress can lead to symptoms similar to depressive disorders. Examining the patient’s history and context for depressive symptoms can help distinguish a major depressive episode from normal grief.20

Other diagnoses that should be considered prior to making a diagnosis of premenstrual dysphoric disorder (PMDD) include:

Premenstrual syndrome

Premenstrual syndrome is generally considered to be less severe than PMDD and does not require a minimum of 5 symptoms for diagnosis.20


Dysmenorrhea is characterized by pelvic pain during menstruation, and does not include the affective symptoms prior to menstruation.20,104

Hormonal treatments

If PMDD symptoms occur after the initiation of hormonal therapy, the symptoms may be due to the use of hormones. Similarly, if cessation of hormonal therapy coincides with a decline in symptoms, the hormonal therapy may be the cause.20

Bipolar disorder or other depressive disorders

The affective symptoms of PMDD can appear similar to bipolar disorder or other depressive disorders. Menses can also worsen preexisting bipolar and depressive symptoms.105,106 This can make it difficult to distinguish PMDD from bipolar disorder or depressive disorders. PMDD is characterized by symptoms that follow a pattern, starting a few days before the period and resolving shortly after the period starts.20 It may be helpful to have patients chart their symptoms over a period time in order to identify a pattern, especially as retrospective recall of symptoms may be unreliable for an accurate diagnosis of PMDD.20

Hyper- and hypo-thyroidism

These diagnoses can be distinguished by symptoms that are not associated with PMDD. For hyperthyroidism, these include weight loss, heat intolerance, disturbances to the heart rhythm, and hyperreflexia. For hypothyroidism, differential symptoms include constipation, cold intolerance, dry skin, and delayed deep tendon reflexes.107 Thyroid tests can also rule out a PMDD diagnosis.108


Anemia can be distinguished from PMDD through a complete blood count test.108

Generalized anxiety disorder

While symptoms can overlap between both disorders, symptoms of generalized anxiety disorder do not fluctuate with the menstrual cycle and may include heart palpitations and feelings of fear, which are not symptoms of PMDD.107

Menstrual migraine

PMDD occurs in relation to ovulation and resolves shortly after the start of menstruation, while menstrual migraines can occur throughout menstruation and in the absence of ovulation.109

In addition, endometriosis may produce symptoms similar to PMDD and should be considered.110 It can be differentiated by examining the history of symptoms and making a physical examination.

Psychiatric Comorbidities

Depressive disorders can also be comorbid with other mental and medical conditions, many of which can have similar symptoms. It is important that patients receive accurate diagnoses so that they can receive proper treatment.

People with major depressive disorder may have additional psychiatric conditions. The estimated prevalence of some additional psychiatric comorbidities in major depressive disorder are as follows: anxiety disorders, 75%; obsessive-compulsive disorder, 40.7% ; substance-use disorder, 25%; personality disorders, 7.6%; borderline personality disorder, 4.1%. References 20 and 112 through 115]

Eating disorders are known to be connected to major depressive disorder, but most research has focused on depressive symptoms in patients with eating disorders, rather than eating disorders in patients with depressive symptoms.

17.4% of patients with major depressive disorder have symptoms of binge eating. Reference 116. 50 to 75% of people with anorexia also experience major depressive disorder during their life. References 20 and 117. 9.4 to 21.2% of women with major depressive disorder also had bulimia nervosa. References 20 and 118. 17.8% of patients with atypical depression also had bulimia nervosa. Reference 119.]

People with PMDD may also have major depressive disorder with an estimated prevalence of 12 to 69%. Reference 120. Another potential comorbidity is bipolar disorder: A small community sample of 74 people with PMDD found that 5.7% also had bipolar I disorder and 4.9% also had bipolar II disorder. Reference 121.]

People with PMDD may also have premenstrual exacerbation: While a range of medical and mental disorders may worsen during the premenstrual phase, this exacerbation alone does not qualify as a diagnosis of PMDD. PMDD may increase the symptom severity of preexisting medical or mental disorders in the week prior to menstruation, but also causes additional symptoms that are not present outside the premenstrual period.20,105,119

Distinguishing symptoms of depressive disorders from other mental and physical disorders can be challenging. However, your dedication to finding the right diagnosis will be beneficial to improving your patients’ well-being.

Treatment Guidelines

Although commonly seen in clinical practice, depressive disorders are difficult to identify. Out of every 100 people screened, 15 people may be misdiagnosed with a depressive disorder, and 10 people with a depressive disorder may be overlooked.80 Delays in treatment can prolong symptoms and lead to long-term adverse effects on brain function.60 However, diagnosis and adequate treatment soon after illness onset can greatly improve a patient’s prognosis.60

The treatment guidelines listed below were selected using an objective and systematic, but not exhaustive, process (see below for the methodology used). These guidelines are for educational use only. Abbvie Inc was not involved in the development of the guidelines listed below and does not endorse the use of any specific guidelines. As NP Psych Navigator is a resource for US healthcare providers, we have only included guidelines from US based organizations. They are provided here for your convenience in alphabetical order. Healthcare providers should use their clinical judgement to determine which guidelines are appropriate for use in their clinical practice. 

Guidelines for Adolescent Depression in Primary Care (GLAD-PC)121,122

  • Supporting organizations: Center for the Advancement of Children’s Mental Health at Columbia University, the Sunnybrook Health Sciences Center at the University of Toronto, the New York Forum for Child Health, the New York District II Chapter 3 of the American Academy of Pediatrics, and the Resource for Advancing Children’s Health Institute
  • Published: 2018
  • Description: These guidelines were borne of a North American academic, governmental, and nonprofit initiative that included various invited pediatric and adolescent mental health experts. Designed to apply to patients aged 10–21 years with major depressive disorder, these guidelines were developed from a combination of a systemic literature review, patient and family focus groups, and a survey of experts. The guidelines included recommendations for assessment and diagnosis, initial management and ongoing treatment with both pharmacological and psychosocial therapies, monitoring and addressing risk factors for suicide, and evaluating the safety and efficacy of treatments. They also addressed primary care clinicians’ qualifications by encouraging training, consulting with mental health specialists as necessary, and using the collaborative-care model. The guidelines were published in two parts.
  • Grading: Treatment recommendations were evaluated using a 5-point system in which 1 indicated the strongest evidence and 5 the weakest evidence, as well as by expert consensus among members of the steering committee. These guidelines included steering committee recommendations with a strong (> 70%) or very strong agreement (> 90%).

Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients with Major Depressive Disorder: A Clinical Practice Guideline from the American College of Physicians123 

  • Supporting organizations: American College of Physicians
  • Published: 2016
  • Description: This guideline was created using a comprehensive literature review and evaluation by the American College of Physicians Clinical Guidelines Committee. The guideline compared second-generation antidepressants with psychotherapy, complementary and alternative medicine, and physical exercise and activity for the treatment of depression. Treatments were evaluated for effectiveness and safety.
  • Grading: Recommendations were made using a modified GRADE system and employed two metrics: benefits versus risks and burdens (“strong” or “weak”), and methodological quality of supporting evidence (“low”, “medium”, or “high”). A grade of “insufficient” could be given if the balance of benefits and risks could not be determined, or if the evidence was conflicting, poor quality, or lacking.

Practice Guideline for the Treatment of Patients with Major Depressive Disorder124

  • Supporting organizations: American Psychiatric Association
  • Published: 2010
  • Description: This guideline was developed by a working group of research and clinical psychiatrists experienced with major depressive disorder. The work group performed a comprehensive literature review to develop recommendations, which were then reviewed by an internal steering committee and independent reviewers. The guideline used the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and was designed to be used for adults who had already been diagnosed with major depressive disorder. The guideline provided a step-by-step plan for appropriate disease management from diagnosis through long-term treatment, including treatment setting, functional impairment, and involvement of a coordinated care team and the patient’s family. Specific recommendations were given for acute management through continuation and maintenance. Factors that could influence a treatment plan were addressed, including suicide risk, cognitive dysfunction, depressive subtypes, psychiatric and physical comorbidities, and demographic variables such as age, sex, culture, and family history. Treatment recommendations consisted primarily of pharmacotherapy and psychotherapy, although alternative physical and nutraceutical treatments were also addressed.
  • Grading: Three levels of endorsement were used. Level I indicated substantial clinical endorsement, level II indicated moderate clinical confidence, and level III indicated that a recommendation may be appropriate in individual circumstances.

Methodology for Guideline Selection

On April 27, 2020, the following search string was entered into the PubMed database:

(depression[Title/Abstract]) OR major depressive disorder [Title/Abstract]) AND (treatment[Title/Abstract]) AND (guideline*[Title] OR guidance[Title]). The search was limited to PubMed, the most commonly used medical publications database in the world, to ensure that this list can be consistently maintained and updated. 

Results were restricted to those publications from the year 200 to the date of the search, those published in English, and those indexed as article type "Practice Guideline". This search returned 70 results. These results were screened in depth according to the following exclusion criteria: articles that were not guidelines for clinical practice, such as research or study results, guidelines that had a published updated (ie, only the most recent version of a set of guidelines was included), guidelines from any entity other than an established, professional clinical organization or a group of said organizations, guidelines from any non-US organization, guidelines that did not report their process for grading and evaluating recommendations, guidelines written for the use of a specific pharmacological or nutraceutical treatment, guidelines that are not available for free, guidelines for depressive disorders secondary to another condition, and guidelines for conditions other than a depressive disorder. In cases where a more recent version of a guideline was available, the newest version was used.

The list will be updated annually.

Non-Pharmacological Management for Major Depressive Disorder

Major depressive disorder is a lifelong illness, but it does not have to be sole the focus of your patients’ lives. Patients can follow non-pharmacological approaches to treatment and lifestyle modifications that can help with managing major depressive disorder. By educating your patients about these additional treatment options, you can help them feel more in control of their mental health. 

What are the potential benefits of psychotherapy?

Research shows that psychotherapy in conjunction with medication may reduce symptoms of major depressive disorder and enhance well-being.125-127 Many types of therapy have been shown to have similar benefits 128:

  • Cognitive-behavioral therapy
  • Behavioral action therapy
  • Psychodynamic therapy
  • Problem-solving therapy
  • Interpersonal therapy
  • Mindfulness-based therapy

Help guide your patients in determining their preferences and treatment goals to choose the psychotherapy style and practitioner that fits them best.126

Researchers have shown that bright light therapy may help reduce depressive symptoms for both seasonal and non-seasonal major depressive disorder.126,129,130

Which lifestyle modifications can help with major depressive disorder?

While taking medications is often the first step in treating major depressive disorder, medication can take time to start showing potential effects, and it can take time to find the right medication.128,129 Your patients can make additional changes that may help manage their major depressive disorder. Research studies indicate there may be an association between positive lifestyle modifications and a potential reduction of depressive symptoms. However, the reasons for which they are beneficial for some people with major depressive disorder but not others remain unclear. Discussing these changes with your patients, along with ways in which they can make these changes, can help them make the right choices for their individual needs. 


Cardiovascular exercise and weight loss can help combat and prevent major depressive disorder.133-137 Physical activity may reduce inflammatory processes, possibly through modulating the gut microbiota.138-140 

Healthy diet

Reduced consumption of saturated fats, refined and added sugars, fried foods, and processed meats is associated with a reduced risk for major depressive disorder. Maintaining a diet of whole and fiber-rich foods (including the Mediterranean diet) may help protect against major depressive disorder.141-144 This potential benefit has also been seen for the recurrent depressive episodes experienced by patients with bipolar disorder.145

Sleep hygiene

Poor sleep increases the risk of major depressive disorder.146Practicing good sleep hygiene, such as staying on a regular sleep schedule147, can help treat and protect against depressive symptoms. Cognitive behavior therapy can help with insomnia, which may lead to a decrease in depressive symptoms.146

Pain management

Body aches and pains can be a result of major depressive disorder.20 Higher levels of pain also increase the risk of major depressive disorder 148 and are associated with poor treatment outcomes.149 Good pain management can help treat and protect against major depressive disorder.150


Some research has indicated that mindfulness practices such as meditation can help with mood symptoms and insomnia .151-153


Moderate caffeine use may reduce the risk of developing major depressive disorder in some individuals, but using caffeine can lead to insomnia, a risk factor for depressive symptoms.154,155

Substance use

While cigarettes and alcohol are addictive and quitting may be difficult, using these substances increases the risk of major depressive disorder. Major depressive disorder can also increase the chances of using alcohol or cigarettes, and their use can worsen depressive symptoms. 156-159


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