Depressive Disorders

Definition AND EpidemiologyTop

The group of depressive disorders share a common set of symptoms including periods of either low mood or loss of pleasure (anhedonia) and are accompanied by sleep changes, feelings of guilt, low energy, poor concentration, appetite changes, psychomotor slowing or agitation, and suicidal ideation.

In the fifth edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5), depressive disorders are classified into:

1) Major depressive disorder (MDD), single and recurrent episodes.

2) Persistent depressive disorder (previously “dysthymia”).

3) Premenstrual dysphoric disorder.

4) Substance/medication-induced depressive disorder.

5) Depressive disorder due to another medical condition.

6) Other specified depressive disorder.

7) Unspecified depressive disorder.

MDD (or “depression,” as it is commonly known) is a debilitating condition that affects many people worldwide. Average lifetime prevalence rates have been reported between 11.1% and 14.6%.

In terms of disability, unipolar depression (depression in the absence of hypomania or mania) was ranked in 2019 by the World Health Organization (WHO) as the first leading cause of years lost to disability (YLD), as well as the fourth highest leading cause of all disability-adjusted life years (DALYs) among those aged 10 to 24 years and sixth among those aged 25 to 49 years. In those groups it was responsible for 3.7% and 3.5% of all DALYs, respectively.Evidence 1Moderate Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020 Oct 17;396(10258):1204-1222. doi: 10.1016/S0140-6736(20)30925-9. Erratum in: Lancet. 2020 Nov 14;396(10262):1562. PMID: 33069326; PMCID: PMC7567026.

Clinical Features And DiagnosisTop

Screening for Major Depressive Disorder

1. It is important to accurately recognize, diagnose, and treat depression.

2. Depressed patients do not always present with mood complaints. A substantial proportion of depressed patients present only with somatic complaints.Evidence 2Moderate Quality of Evidence (moderate confidence that we know the true relationship). Quality of Evidence lowered due to unexplained heterogeneity among centers. Simon GE, VonKorff M, Piccinelli M, Fullerton C, Ormel J. An international study of the relation between somatic symptoms and depression. N Engl J Med. 1999 Oct 28;341(18):1329-35. PubMed PMID: 10536124.

3. Goals of assessment include establishing rapport, evaluating for safety, assessing for comorbidities, and providing patient education.

4. Screening for depression can be done using several tools, which have been shown to be moderately but equally effective. They include:

1) Patient Health Questionnaire (PHQ-9): Examples of the PHQ-9 and 2-stem questionnaire: Table 1, Table 2. The 2-stem question instrument is a highly sensitive screen for depression (98% sensitivity, 86% specificity), however the 9-item questionnaire allows for assessing the response to treatment at follow-up visits by showing the change in the total score.

2) Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR).

3) Beck Depression Inventory first (BDI-I) or second (BDI-II) edition.

4) Zung Self-Rating Scale.

5) Center for Epidemiologic Studies-Depression (CES-D) scale.

5. For specific populations, other screening tools include the Geriatrics Depression Scale and the Edinburgh Postnatal Depression Scale.

Diagnosing Depression

According to the DSM-5, a diagnosis of MDD requires the presence of ≥5 symptoms, of which at least 1 must be either depressed mood or anhedonia. Additional symptoms may include sleep changes, feelings of worthlessness or guilt, low energy, poor concentration, appetite changes, psychomotor slowing or agitation, and suicidal ideation. These symptoms must continue for 2 weeks, cause significant distress or functional impairment, and not be better explained by other mental disorders, other medical disorders, or the effect of a substance. These criteria constitute a major depressive episode (MDE). One or more major depressive episodes make up MDD.

Differential diagnosis includes other psychiatric conditions, medical conditions, and substance use.

Mild depression is defined in the DSM-5 as “few, if any, symptoms in excess of those required” for the diagnosis. The intensity of symptoms is “manageable” and there is “minor impairment” in functioning.

Moderate depression according to the DSM-5 refers to situations where the intensity and impairment due to depressive symptoms fall between mild and severe.

Severe depression according to the DSM-5 refers to situations where “the number of symptoms is substantially in excess of that required” for the diagnosis, the symptoms are “seriously distressing and unmanageable,” and they “markedly interfere” with functioning.

Other Forms of Depression

Depressive symptoms occur in a number of mental disorders. In medical settings, adjustment disorder with depressed mood and MDD are the most commonly seen. Adjustment disorders occur in response to a stressor, with symptoms of marked distress or impaired functioning. Symptoms must develop within 3 months of the stressor occurring and should resolve within 6 months of the stressor ending.

Although MDD can also occur after a stressor, the key difference between MDD and adjustment disorder is whether the patient perceives their low mood would remit if the stressor were removed. In adjustment disorder the removal of the stressor would lead to remission of depressive symptoms. In MDD the removal of the stressor might improve symptoms marginally but not completely.

Risk FactorsTop

Risk Factors in the Development of Depression

A number of risk factors have been identified in the development of depression. Risk factors include female sex, chronic medical conditions, sleep disorders, low socioeconomic status, recent bereavement, positive family history, childhood maltreatment history, and substance use. Further information about the strength of those associations: Table 3.

In elderly patients, risk factors for depression include institutionalized living, dementia, female sex, chronic disease, and sensory impairment. It should be also noted that the elderly are also at risk for suicide.

Depression due to a General Medical Condition

Some medical conditions cause symptoms that overlap with those of depression and can be said to mimic depression (eg, hypothyroidism), while others appear to increase the risk of developing depression or may have a joint factor that causes depression (eg, multiple sclerosis).

It is important to screen each patient for other simple causes of depressive symptoms that are plausible within each patient’s own context and treat the underlying condition when possible. Treatment of depression should be considered when depressive symptoms appear to be interfering with functioning and persist despite treatment of the underlying medical condition.

Medical conditions that may be associated with depressive symptoms include anemia (particularly in the elderly), hypothyroidism, stroke, Parkinson disease, Huntington disease, Alzheimer disease, traumatic brain injury, multiple sclerosis, systemic lupus erythematosus, neoplasm, HIV, cytokine-induced sickness behavior, and delirium.

Medication-Induced Depression

In the literature, there are several reports of medications causing depression. However, most claims are not supported by high-quality evidence.

There is low-quality evidence suggesting that a variety of medications may cause or be associated with depressive symptoms, including barbiturates, vigabatrin, topiramate, flunarizine, glucocorticoids, mefloquine, efavirenz, and interferon alpha.

Because individual response to treatment varies between patients, if depressive symptoms are noted to occur temporally after initiation of a medication and remit when the medication is stopped, consider using another agent.

TreatmentTop

General Considerations

Please remember that depression is not simply “the blues,” and it is not a sign of a character flaw or weak will. The compassionate clinician recognizes that patients with depression will not improve by being advised to “pull themselves together” or to “just get over it.” Depression is a serious illness with profound consequences that can—and should—be treated in this modern era.

Be sure to listen attentively to your patient with compassion and sensitivity, and do not underestimate their complaints. Be advised that the safety of your patient is paramount, and thus, any declaration of suicidal ideation should be assessed carefully, and appropriate action taken when necessary.

It is important to note that there are multiple management options to treating depression, including psychotherapy, pharmacologic approaches, electroconvulsive therapy (ECT), or a combination of these modalities. The following is a more in-depth explanation of management approaches based on the severity of symptoms.

Appropriate management should be individualized to each patient according to:

1) The nature of the disorder (that is, confirm the diagnosis of depression, exclude other causes).

2) The severity of symptoms.

3) Any medical or psychiatric comorbidities (including the possibility of drug-drug interactions and pregnancy).

4) Previous response to treatment (in the patient or other family members).

5) The existing support, resources, preferences, and psychosocial environment of the patient.

The assessment of efficacy of pharmacologic treatment of depression is hampered by short duration of trials, large number of patients not completing studies, and confounding of treatment effect by spontaneous remissions. The treatment effect is also influenced by the various methods of measurement of depressive disorder and outcomes of interests adding to the limitations of the generalizability of trial findings. The overall body of evidence suggests shortening of depressive episodes and possibly prevention of recurrent episodes, especially among patients with previous recurrences. The suggestions include continuation of treatment for up to 12 months after remission and possibly longer or permanently after consecutive relapses. Such relapses are common, and after discontinuation of treatment about one-third of patients will experience relapse of symptoms within 1 year.

Management of Mild Depression

1. Self-care is recommended:

1) NEST-S: “Nutrition, exercise, sleep, time for self, and social support” are effective in the management of mild depression.

2) Behavioral activation: Encourage physical activity.

2. Psychotherapy is effective and recommended in the management of mild depression:

1) Cognitive behavioral therapy (CBT): CBT involves 12 to 16 sessions of psychotherapy treatment that identifies and treats maladaptive behaviors, cognitive distortions, negative schemas, and the cognitive triad of a negative view of self, the world, and the future in order to improve mood symptoms.Evidence 3Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). National Institute for Health and Clinical Excellence. Depression in adults: recognition and management (CG90). Evidence. https://www.nice.org.uk/guidance/cg90/evidence. Published October 2009. Updated April 2016. Accessed August 17, 2016.

2) Behavioral activation therapy (BAT): It is a brief structured therapy that includes a number of sessions (from 2 to 24, usually 12) provided weekly or twice a week in an individual or group format. BAT is a component of CBT; however, the focus is on actions to increase engagement of the patient with their world and increase rewarding behaviors based on the principle that “what you do affects how you feel.” The effects of BAT and CBT on depression are similar.Evidence 4Moderate Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias. Uphoff E, Ekers D, Robertson L, et al. Behavioural activation therapy for depression in adults. Cochrane Database Syst Rev. 2020 Jul 6;7(7):CD013305. doi: 10.1002/14651858.CD013305.pub2. PMID: 32628293; PMCID: PMC7390059.

3) Interpersonal therapy (IPT): Interpersonal therapy is a 12- to 16-session psychotherapy treatment that focuses on improving mood symptoms by identifying and working through distressing life events, which include complicated bereavement (grief), role disputes (interpersonal conflicts), and role transitions.Evidence 5Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. National Institute for Health and Clinical Excellence. Depression in adults: recognition and management (CG90). Evidence. https://www.nice.org.uk/guidance/cg90/evidence. Published October 2009. Updated April 2016. Accessed August 17, 2016.

4) Problem-solving therapy (PST): The theory behind problem-solving therapy is to improve mood by improving patients’ problem-solving skills. The goal of this psychotherapy is to identify the patient’s problems, consider various solutions, decide on the most appropriate solution, prepare a plan to carry out that solution, and assess whether the solution was effective.Evidence 6Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision (especially against or in addition to antidepressants) and heterogeneity of results against different comparators. National Institute for Health and Clinical Excellence. Depression in adults: recognition and management (CG90). Evidence. https://www.nice.org.uk/guidance/cg90/evidence. Published October 2009. Updated April 2016. Accessed August 17, 2016.

5) Self-management resources such as workbooks and websites are suggested when low resources exist for traditional psychotherapy.

3. Free examples developed at Simon Fraser University (www.sfu.ca) include:

1) Antidepressant Skills Workbook (for adults).

2) Antidepressant Skills at Work: Dealing with Mood Problems in the Workplace.

3) Positive Coping with Health Conditions.

4) Managing Depression: A Self-help Skills Resource for Women Living With Depression During Pregnancy, After Delivery, and Beyond.

5) Dealing with Depression (for adolescents).

4. Free interactive websites include the MoodGYM training program.

5. Resources available at cost include:

1) Greenberger D, Padesky, C. Mind Over Mood: Change How You Feel by Changing the Way You Think. New York: Guilford Press; 1995.

2) Beating the Blues (website): www.beatingtheblues.co.uk.

Management of Moderate Depression

Combination therapy of antidepressants and psychotherapy is recommended to increase the probability of remission. First-line treatment may involve drugs from different classes: selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic antidepressants (NaSSAs), bupropion, and reversible inhibitors of monoamine oxidase A (RIMAs), with some suggestion that escitalopram and sertraline have the best balance between efficacy and acceptability.Evidence 7Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the small number of direct comparisons and short duration of many studies. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009 Feb 28;373(9665):746-58. doi: 10.1016/S0140-6736(09)60046-5. Review. PubMed PMID: 19185342. Other useful modalities include different types of psychotherapy (BAT, CBT, IPT, PST), as outlined above.

Management of Severe Depression

1. Combination therapy of antidepressants and psychotherapy is recommended to increase the probability of remission.

2. Major depressive episodes with psychotic features can be treated with a combination of an antidepressant and an antipsychotic medication.

3. ECT should be considered for severe, treatment-resistant depression or depression with psychotic features.

Management of Depression in the Elderly

1. Escitalopram and sertraline are considered first-line antidepressant treatments for the elderly, especially for severe depression, because of efficacy and tolerance.

2. Moderate-intensity exercise (30-minute sessions 3 to 5 times a week for 3 to 4 months) is an effective adjunct for depression treatment in the elderly.

3. Psychotherapy: BAT, CBT, IPT, and PST have shown efficacy.

4. Be mindful of adverse effects, which may be exaggerated in the elderly (eg, polypharmacy interactions, any anticholinergic adverse effects). In general, elderly patients should be started on lower doses of psychotropic medications and dose escalation should occur slowly, with the goal of attaining a therapeutic dose.

Pharmacotherapy

1. Choosing an antidepressant medication: The choice of an antidepressant, when indicated, should be discussed with the patient. The selection should be based on the patient’s preference, type of symptoms, adverse effect profile of the medication, comorbidities, and concomitant medication use. When selecting an antidepressant, most clinicians start with an SSRI, as this class is well tolerated and effective.

1) SSRIs, SNRIs, and newer antidepressants such as bupropion or mirtazapine are considered first-line medications for severe depression.

2) TCAs are considered second-line treatment and monoamine oxidase inhibitors (MAOIs) are considered third-line agents due to their adverse-effect profiles.

A network meta-analysis comparing different antidepressants ranked the following antidepressants as the top 5 based on their efficacy and tolerability: mirtazapine, escitalopram, venlafaxine, sertraline, and citalopram.

Other treatment options exist, such as the addition of second-generation antipsychotics (eg, olanzapine, risperidone, aripiprazole) along with other classes of antidepressants. However, more complex treatment regimens should be used under the supervision of a psychiatrist.

2. Major adverse effects and interactions of antidepressant agents: Table 4.

3. Suggestions for initiating antidepressant medications:

1) Before starting any antidepressant agent, consider completing baseline liver function tests and a metabolic workup, such as screening for diabetes mellitus, dyslipidemia, and thyroid disease.

2) Obtain an electrocardiogram (ECG) to determine any baseline arrhythmias as well as the QTc (which can be prolonged with psychotropic use) prior to initiation of a medication.

3) Consider follow-up every 1 to 2 weeks when titrating an antidepressant. The frequency can then be reduced to every 2 to 4 weeks when a therapeutic dose is reached, depending on the severity of depression and response to treatment.

4) In selecting the appropriate antidepressant agent, patient comorbidities should be taken into account along with any adverse effects of the medications. For example, mirtazapine is associated with increased appetite and weight gain, and therefore may be avoided in patients with obesity and diabetes mellitus.

4. Dosing of common first-line medications effective in treating major depression: Table 5.

5. Assessing treatment response:

1) Initial treatment response: Most clinical trials define clinical response as a ≥50% reduction in the score on a depression rating scale, while clinical remission is defined as a score within the normal range of the scale. Improvement may begin within 1 to 2 weeks of treatment; however, it can take >8 weeks for response and/or remission.

2) Adjusting medication treatment:

a) If there is <20% improvement on one of the depression scales after 2 weeks, consider increasing the dose of medication.

b) If there is ≥20% improvement after 4 to 6 weeks (but not remission), consider an additional 2 to 4 weeks of the same treatment.

c) If there is no further improvement, consider other treatment strategies: nonpharmacologic interventions such as CBT and IPT; switching antidepressants; augmentation (combining an antidepressant with a second medication) under the supervision of a psychiatrist; ECT under the supervision of a psychiatrist.

6. Length of therapy: Pharmacotherapy should be continued for at least 6 months after remission. For those with recurrence of depression or risk factors for recurrence, treatment is recommended to be continued for at least 2 years. Depending on the number of recurrent episodes, longer treatment courses can be considered. Dosing should be continued at the same effective dose, not a reduced dose.

7. Switching antidepressant medicationsEvidence 8Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity of findings, indirectness to today’s modalities, and observational nature of some data. Ruhé HG, Huyser J, Swinkels JA, Schene AH. Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review. J Clin Psychiatry. 2006 Dec;67(12):1836-55. Review. PubMed PMID: 17194261. Han C, Wang SM, Seo HJ, et al. Aripiprazole augmentation, antidepressant combination or switching therapy in patients with major depressive disorder who are partial- or non-responsive to current antidepressants: a multi-center, naturalistic study. J Psychiatr Res. 2014 Feb;49:75-82. doi: 10.1016/j.jpsychires.2013.11.001. Epub 2013 Nov 12. PubMed PMID: 24268719.: No difference exists between switching within the same class of medications versus switching to a different class of medications.

1) The technique for safe switching to a different class of antidepressant agents depends on drug-drug interactions and the pharmacologic properties of the medications. For example, when switching from SSRIs to MAOIs, withdraw SSRIs first and wait for 2 weeks (in the case of fluoxetine, wait for 5 to 6 weeks) before starting MAOIs.

2) If switching an SSRI to venlafaxine, cross-taper cautiously and start venlafaxine at a smaller dose of 37.5 mg.

3) If switching from mirtazapine to a TCA, withdraw mirtazapine first and then start the TCA.

4) When stopping antidepressants, consider reducing the dose gradually over 4 weeks.

8. Tapering medications: Abrupt discontinuation of antidepressant agents can lead to discontinuation symptoms. Common antidepressant discontinuation symptoms include nausea, headache, light-headedness, chills, body aches, insomnia, neurologic symptoms such as paresthesias, and “electric shock-like” phenomena. When stopping antidepressants, consider reducing the dose gradually over 4 weeks if tolerated. Some patients may need a slower reduction over a longer period. Some discontinuation symptoms may mimic the underlying depression symptoms, which may recur on reducing and stopping medications. Medications associated with the highest risk of discontinuation symptoms include paroxetine, venlafaxine, amitriptyline, and clomipramine. Examples of medications with lower risk of withdrawal symptoms include fluoxetine and bupropion.

PrognosisTop

Remission is defined as a period of ≥2 months with no symptoms, or only 1 to 2 symptoms present to no more than a mild degree. It can be expected within 3 months for 60% of patients and within 1 year for 80% of patients, regardless of whether the depression is treated.

Decreased rates of remission are expected if the patient has a comorbid anxiety disorder, personality disorder, psychotic symptoms, or severe symptoms.

The risk of recurrence is higher in young patients, individuals with previous multiple episodes, and in patients whose previous episodes were considered severe.

TablesTop