*Depressive Disorders

Chapter: Depressive Disorders
McMaster Section Editor(s): Robert B. Zipursky, Rebecca Anglin
McMaster Author(s): Janet Song, Avi Ramsaroop, Zainab Samaan
Additional Information

Definition, EpidemiologyTop

Depressive disorders are a group of disorders with a subjectively perceived depressed mood as a dominant symptom (note: this may not be evident). Depressive disorders (in short, depression) may develop in the course of mood (affective) disorder, medical illness, adjustment disorder (depression occurring in the context of a stressor), poisoning and adverse effects of drugs, and other psychiatric disorders. Depression is a debilitating condition that affects many people worldwide. It is also very common: traditionally, average lifetime prevalence rates have been reported between 11.1% and 14.6%. Recent prospective data suggest that prevalence may be even few-fold higher.

As an illness, depression is often characterized by periods of either low mood or loss of interest and pleasure (also known as anhedonia) accompanied by symptoms such as sleep changes (whether hypersomnolence or insomnia), feelings of guilt, low energy, decreased concentration, changes in appetite (whether increased or decreased), psychomotor retardation, and suicidal ideation.

In the fifth edition of 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 (PDD) (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.

In terms of disability, unipolar depression, or depression in the absence of hypomania or mania, was ranked as the first leading cause of years lost to disability (YLD) and the ninth highest leading cause of all disability-adjusted life years (DALYs) in the world in 2012 by the World Health Organization. Responsible for 2.8% of all DALYs, depression caused similar rates of disability when compared to road injury (2.9%) and human immunodeficiency virus/AIDS (3.4%).

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 1Moderate 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 or evaluating patient safety, rapport, comorbidities, providing patient education, and discussing consent to treatment.

4. Screening or case-finding for depression can be done using several tools, which have been shown to be moderately but equally effective. They include the nine-question Patient Health Questionnaire (PHQ-9), Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR), Beck Depression Inventory first (BDI-I) or second (BDI-II) edition, Zung Self-Rating Scale, and Center for Epidemiologic Studies-Depression (CES-D) scale. 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.

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

Diagnosing Depression

According to the DSM-5, major depressive disorder diagnosis requires the presence of 5 or more symptoms of depression, of which at least one is either low/depressed mood or loss of interest and pleasure in previously enjoyed activities (anhedonia). Additional symptoms may include changes in appetite or weight, changes in sleep, psychomotor agitation or retardation, fatigue, feelings of worthlessness or guilt, impaired concentration, and suicidal ideation. These symptoms should be of at least 2-week duration, cause significant distress or functional impairment, and represent a clear change from the previous state.

It is prudent to make sure such episodes are not due to other psychiatric or medical condition (eg, schizophrenia, endocrine disturbances [eg, thyroid or parathyroid, adrenal]). The differential diagnosis should also include reaction to loss, adjustment disorder, or substance use.

A depressive episode is the most common form of depression. It may occur in the course of recurrent depression or bipolar disorder, which also includes episodes of mania or hypomania.

Mild depression is defined in the DSM-5 as few if any symptoms present in addition to those required for a diagnosis of a depressive episode. The intensity of symptoms is manageable.

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 greater than the minimal number required for the diagnosis, and the impairment and distress are unmanageable.

Other Forms of Depression

There are several forms of depression; however, a depressive episode as described above and adjustment disorder with depressed mood are commonly seen in medical settings. Adjustment disorders occur in response to a stressor and represent an excessive or abnormal reaction to the stressor that results in significantly impaired functioning. Symptoms develop within 3 months of the onset of the stressor and can last less than 6 months (acute) or longer than 6 months (persistent/chronic). Patients with adjustment disorder present with marked distress and may have depressed mood, anxiety, and disturbance of conduct (changes in behavior, acting out). By definition, when the stressor has terminated the symptoms do not persist for more than an additional 6 months.

The difference between the adjustment disorder and a depressive episode lies in the evident relationship of the current mood with the occurrence of a certain problem. When the patient’s attention is shifted away from the source of the problems, he or she may regain the ability to derive satisfaction from the personal growth/development.

Risk FactorsTop

Risk Factors in the Development of Depression

A number of risk factors have been identified in the development of depression. It would be prudent for the clinician to be aware and take note of any of these risk factors in their patients and provide the appropriate support wherever possible. Risk factors include female sex, chronic medical conditions, sleep disorders, low socioeconomic status, recent bereavement, positive family history, childhood maltreatment history, and substance use and addictions. Further information about the strength of those associations: Table 3.

In the 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 at risk for suicide: in 2011, there were 517 deaths by suicide in Canada.

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, while others appear to increase the risk of developing depression or cause depression.

Clinicians ought 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, human immunodeficiency virus (see AIDS), 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 depression symptoms are noted with any medication, you may consider another agent.

TreatmentTop

General Considerations

Please remember that depression is not simply “the blues,” and it is certainly not a sign of a weak will or character flaw. 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, 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 probability of 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.

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 2Strong 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) 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 dispute (interpersonal conflict), and role transition.Evidence 3Weak 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.

3) 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 4Weak 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.

4) 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 5Moderate 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 (CBT, IPT, PST).

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 also be treated with a combination of an SSRI 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.

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: 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.

Pharmacotherapy

1. Choosing an antidepressant medication: The choice of an antidepressant when indicated should be discussed with the patient, and the selection should be based on the patient’s preference, type of symptoms, adverse-effect profile, comorbidities, and concomitant medications. When selecting an antidepressant, start with an SSRI, keeping in mind the associated risks and adverse effects.

1) SSRIs, SNRIs, and newer antidepressants such as bupropion or mirtazapine are considered the first-line medications for severe depression, as opposed to tricyclic antidepressants (TCAs). Compared to placebo, patients using SSRIs show a reduction of symptoms but no difference in the remission or dropout rates (from studies) after 6 to 8 months of follow-up.

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 top 5 antidepressants based on their efficacy: mirtazapine, escitalopram, venlafaxine, sertraline, and citalopram. This list is not exhaustive. Other treatment options exist, such as second-generation antipsychotics (eg, olanzapine, risperidone, aripiprazole) and other classes of antidepressants.

Individualized treatment should be selected depending on the patient’s characteristics, such as risk for metabolic syndrome, drug interactions, and drug response.

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

3. Suggestions for initiating antidepressant medications:

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

2) Consider follow-up every 1 to 2 weeks when starting pharmacotherapy. The frequency can then be reduced to every 2 to 4 weeks, depending on the severity of depression and response to treatment.

3) Consider electrocardiography (ECG) when treating patients with comorbid cardiac conditions or when starting medications with the potential to induce arrhythmias.

4) In selecting the appropriate antidepressant agent, patient comorbidities should be considered along with adverse effects of the medications; for example, medications such as mirtazapine are associated with increased appetite and weight gain and therefore it is suggested to avoid them 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 the “clinical response” as ≥50% reduction in the score on a depression rating scale and “clinical remission” 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 depression scales after 2 weeks, consider other treatment strategies or increasing the dose of medications.

b) If there is ≥20% improvement after 4 to 6 weeks without remission, consider additional 2 to 4 weeks of the same treatment.

c) If there is no improvement, consider other treatment strategies:

Augmentation (combining an antidepressant with a second medication): Lithium or second-generation antipsychotics can be offered to partial responders. Buspirone and bupropion may also be effective.

Switching antidepressants.

Nonpharmacologic interventions such as CBT and IPT.

ECT may be an option for patients with poor response to pharmacotherapy, as antidepressant medication treatment failure does not predict lower remission rates with ECT.

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 medications:Evidence 6Low 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 withdrawal symptoms. Common antidepressant withdrawal symptoms include nausea, headache, light-headedness, chills, body aches, and neurologic symptoms such as paresthesias, insomnia, and “electric shock-like” phenomena.

It is advised to taper down the dose over several weeks for most antidepressants; however, this may vary depending on the half-life or presence of serious adverse effects.

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 (both those receiving and not receiving treatment).

Decreased rates of remission are expected if the patient has comorbid anxiety or personality disorder or severe or psychotic depressive 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

Table 1. Screening for depression: 9-question Patient Health Questionnaire (PHQ-9)

Question

Score

Over the last 2 weeks, how often have you been bothered by any of the following problems?

1. Little interest or pleasure in doing things

2. Feeling down, depressed, or hopeless

3. Trouble falling or staying asleep, or sleeping too much

4. Feeling tired or having little energy

5. Poor appetite or overeating

6. Feeling bad about yourself or that you are a failure or have let yourself or your family down

7. Trouble concentrating on things, such as reading the newspaper or watching television

8. Moving or speaking so slowly that other people could have noticed. Or the opposite: being so fidgety or restless that you have been moving around a lot more than usual

9. Thoughts that you would be better off dead or of hurting yourself in some way

Each criterion is scored as “0” (not at all) to “3” (nearly every day).

A total score ≥10 has a sensitivity of 88% and a specificity of 88% for major depression.

Table 2. Screening for depression: 2-stem questions instrument

During the past month, have you often been bothered by feeling down, depressed, or hopeless?

During the past month, have you often been bothered by little interest or pleasure in doing things?

Answering “no” to both of these questions is effective in excluding depression.

Table 3. Risk factors for development of depression

Individual

Psychological

Chronic medical condition

(9.3%-23.0% of patients with chronic physical disease have comorbid depression compared to 3.2% without chronic disease; P <0.0001)

CHF (OR, 1.96; 95% CI, 1.23-3.11)

HTN (OR, 2.00; 95% CI, 1.74-2.31)

DM (OR, 1.96; 95% CI, 1.59-2.42)

CAD (OR, 2.30; 95% CI, 1.94-2.68)

CVA (OR, 3.15; 95% CI, 2.33-4.25)

COPD (OR, 3.21; 95% CI, 2.72-3.79)

ESRD (OR, 3.56; 95% CI, 2.61-4.87)

Any chronic condition (OR, 2.61; 95% CI, 2.31-2.94)

Migraine (RR, 1.53; 95% CI, 1.35-1.74)

Headache (RR, 1.44; 95% CI, 1.32-1.56)

Cancer (HR, 3.55; 95% CI, 2.79-4.52)

Chronic lung disease (HR, 2.21; 95% CI, 1.64-2.79)

Heart disease (HR, 1.45; 95% CI, 1.09-1.93)

Arthritis (HR, 1.46; 95% CI, 1.11-1.92)

Maltreatment in childhood

Emotional abuse (F/M: OR, 2.7/2.5; 95% CI, 2.3-3.2/1.9-3.2)

Physical abuse (F/M: OR, 2.1/1.6; 95% CI, 1.8-2.4/1.4-1.9)

Sexual abuse (F/M: OR, 1.8/1.6; 95% CI, 1.5-2.0/1.3-2.0)

Witnessed interpersonal violence (F/M: OR, 2.1/1.5; 95% CI, 1.8-2.5/1.2-1.9)

Female sex (OR, 1.83; 95% CI, 1.43-2.35; P <0.001)

Stressful life events

Sleep disorder

Insomnia (OR, 4.0; 95% CI, 2.2-7.0)

Hypersomnia (OR, 2.9; 95% CI, 1.5-5.6)

Recent bereavement (10%-20% of bereaved population develop clinical depression)

Positive family history

One parent affected (OR, 2.7; 95% CI, 2.1-3.5)

Two parents affected (OR, 3.0; 95% CI, 2.2-4.1)

Substance use and addictions

Ethanol (OR, 1.50; 95% CI, 1.17-1.92; P <0.001)

Marijuana (OR, 1.41; 95% CI, 1.21-1.65; P <0.001)

Other illicit drugs (OR, 1.65; 95% CI, 1.34-2.02, P <0.001)

Low socioeconomic status (low education/income/social status/combination) (OR, 1.81; 95% CI, 1.57-2.10, P <0.001)

CAD, chronic artery disease; CHF, chronic heart failure; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; DM, diabetes mellitus; ESRD, end-stage renal disease; F, female; HR, hazard ratio; HTN, hypertension; M, male; OR, odds ratio; RR, relative risk.

Table 4. Major adverse effects and interactions of different classes of antidepressant agents

Class

Examples

Major adverse effects

Selective serotonin reuptake inhibitors (SSRIs)

(Considered second generation)

Citalopram

Escitalopram

Fluoxetine

Paroxetine

Sertraline

Suicidal ideation, CNS, GI upset, weight gain, sexual dysfunction, hyponatremia, serotonin syndrome, bleeding risk (especially when combined with NSAIDs)

Fluvoxamine

(Considered second generation)

(Belongs to SSRI class but is less commonly used for depression)

SSRI adverse effects +/- palpitations, tachycardia, malaise, sedation

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

(Considered second generation)

Desvenlafaxine

Duloxetine

Venlafaxine

GI, weight gain, CNS, sexual dysfunction, dermatologic

Noradrenergic and specific serotonergic antidepressants (NaSSAs)

(Considered second generation)

Mirtazapine

Increased appetite, weight gain, postural hypotension, drowsiness

Bupropion

(Considered second generation)

GI, CNS, dermatologic

Tricyclic antidepressants (TCAs)

(Considered first generation)

Amitriptyline

Desipramine

Imipramine

Nortriptyline

Arrhythmias, CNS, sedation, anticholinergic, endocrine, hyponatremia, GI, weight gain; high lethality with overdose

Reversible inhibitors of monoamine oxidase A (RIMAs)

(Considered second generation)

Moclobemide

Sleep disturbances, CNS, GI, dermatologic

Monoamine oxidase inhibitor (MAOI)

(Considered first generation)

Phenelzine

Postural hypotension, sleep disturbances, CNS, GI, fetal malformations; can cause hypertensive crisis when combined with certain foods and medications, in particular other antidepressants (eg, during tapering course)

CNS, central nervous system; GI, gastrointestinal tract; NSAID, nonsteroidal anti-inflammatory drug.

Table 5. Dosing of common first-line medications shown to be effective in treating major depression (based on British National Formulary [BNF] 72)

Medication

Starting dose (mg/d)

Usual dose (mg/d)

Selective serotonin reuptake inhibitors

Citalopram

20

20-40

Escitalopram

10

10-20

Fluoxetine

20

20-60

Paroxetine

20

20-50

Sertraline

50

50-200

Serotonin-norepinephrine reuptake inhibitors

Venlafaxine, immediate release

75

75-375

Venlafaxine, extended release

75

75-375

Duloxetine

60

60-120

Norepinephrine-serotonin modulator

Mirtazapine

15

15-45

Dopamine-norepinephrine reuptake inhibitor

Bupropion, immediate release

150

300-450

Bupropion, sustained release

150

300-400

Bupropion, extended release

150

300-450

For some of these medications (such as tricyclic antidepressants), the upper dosing limit reflects risk of toxicity or need for plasma level assessment, whereas others (such as selective serotonin reuptake inhibitors) can be used safely at higher doses.

Elderly patients, patients with anxiety disorders, patients with liver disease or other major medical comorbidities should receive a lower starting dose.

Starting doses should be increased gradually until therapeutic dose is reached or the patient achieves remission.

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