MAJOR DEPRESSIVE DISORDER (MDD)

Epidemiology

The World Health Depression is also an

Organization (WHO) independent risk factor
reported depression for increased morbidity
as the leading cause and mortality from
of disability worldwide cardiac disease
Risk Factors: MDD
Family History
• Strong family history of depression, suicide or
Age/Sex suicide attempts, alcohol abuse, or other substance
• Peak age: Mid- to late abuse History
adolescence to the early 40s • Adverse childhood events (ACEs)
Female • Current Medical Condition
• Current chronic disease (especially multiple
diseases)
• Chronic pain Insomnia

Life Events That Affect Mood

• Stress
• Social determinants of health such as unemployment, poor education,
food and housing instability, limited access to health care
• Recent traumatic event
• Retirement
PATHOPHYSIOLOGY
• People with depression have reduced serotonin transmission
• A functional polymorphism in the serotonin transporter gene (5-HTT) may interact with stressful
life events to markedly increase the risk for depression and suicide, especially when the
stressors are encountered early in life. Norepinephrine, which increases heart rate, blood
pressure, and blood sugar in the body, may be seen in low levels in depression.
• Low levels of dopamine will be demonstrated through feelings of boredom and apathy, loss of
satisfaction, and chronic fatigue.
• Some of the findings indicate volume reductions in the thalamus, basal ganglia,
hippocampus, prefrontal cortex, and orbitofrontal cortex, and possibly the amygdala and
anterior cingulate cortex.
• Unclear what contributes to the changes in volume. Continued studies have supported a
network of brain areas altered in depression. As brain imaging continues to improve, better
understanding of how the different regions interact will be better understood. Alterations in
sleep, appetite, and sexual behavior, as well as biological changes in endocrine,
immunological, and chronobiological measures in patients with depression, all suggest
dysregulation of the hypothalamus.
Contributing Factors to MDD

Approximately 5% to 10% of all patients with depression have a coexisting

thyroid disorder.

Genetic factors are strongly Implicated in the development of depressive

disorders (Twin studies)

Stressful life events commonly precede first episodes of mood disorders. Some
speculate that the stress accompanying the first episode results in long-lasting
changes in neurocircuitry. ( loss of a parent before age 11, unemployment)
Patient Presentation

People use the term depression to describe a wide variety of negative

emotional states, ranging from sadness to loss of interest or pleasure in
activities to irritability to self-hate.

often present with ambiguous symptoms of

The hallmarks of MDD, unexplained fatigue, changes in appetite, and changes
however, are sadness and in sleep patterns; only when questioned will they admit
to feelings of “sadness.” Others will complain of
anhedonia (loss of moderate to significant feelings of apathy. Additional
pleasure). presentations include complaints of irritability, anger,
anxiety, or hyperactivity.

Many people with depression are unaware of the level of functional impairment
resulting from their illness. Slowed thinking and emotional numbness—two
significant symptoms of depression—can contribute to a lack of awareness of
depression.
Patient Presentation

MDD is characterized by substantial negative changes in mood, thinking,

and behavior. A person who is severely depressed will have intense
feelings of sadness, irritability, or apathy. These feelings may persist and
are unrelieved by situational changes; for example, whether at home,
school, work, or in recreational situations, the mood of the person with
depression will vary little, without significant improvement.

Negative views can seem more valid than positive views. Global negative
thinking can take on a ruminative or circular pattern, so that the person’s
negative thinking seems to always depart from and arrive at the same
painful conclusions.
Patient Presentation

MDD interferes with decision making and

concentration negative thinking may include thoughts
of death and suicide may begin behaving
uncharacteristically
• Depression-related behavioral changes range from changes in
grooming and interpersonal interactions to substance abuse,
irritability, aggression, and social withdrawal.
Evaluating for MDD-Patient Health
Questionnaire (PHQ)-Testing
• Have you felt down or hopeless over the past few weeks?
• Have you had little interest in doing things over the past few weeks?
• If positive further testing with the clinical diagnosis of MDD can be assisted
by the Patient Health Questionnaire-9 (PHQ-9). Its sensitivity (85%) and
specificity (84%) make it an excellent tool to utilize in primary care.
Consisting of a checklist of nine symptoms, the PHQ-9 provides an effective
supplement to the two-question screen.
• Other scales frequently employed include the Geriatric Depression Scale
(GDS), a widely used and validated screening tool for use in older adults.
The Edinburgh Postnatal Depression (EPSD) scale is one of the most used
screening tools for PPD
 PHQ-9 depression questionnaire
Name: Date:
Over the last 2 weeks, how often have you been bothered by
Not at all Several days More than half the days Nearly every day
any of the following problems?

Little interest or pleasure in doing things 0 1 2 3

Feeling down, depressed, or hopeless 0 1 2 3
Trouble falling or staying asleep, or sleeping too much 0 1 2 3
Feeling tired or having little energy 0 1 2 3
Poor appetite or overeating 0 1 2 3
Feeling bad about yourself, or that you are a failure, or that you
0 1 2 3
have let yourself or your family down

Trouble concentrating on things, such as reading the newspaper or

0 1 2 3
watching television

Moving or speaking so slowly that other people could have noticed?

Or the opposite, being so fidgety or restless that you have been 0 1 2 3
moving around a lot more than usual.

Thoughts that you would be better off dead, or of hurting yourself in

0 1 2 3
some way

Total ___ = ___ + ___ + ___ + ___

PHQ-9 score ≥10: Likely major depression

Depression score ranges:
5 to 9: mild
10 to 14: moderate
15 to 19: moderately severe
≥20: severe
If you checked off any problems, how difficult have these
Not difficult at all Somewhat difficult Very difficult Extremely difficult
problems made it for you to do your work, take care of
___ ___ ___ ___
things at home, or get along with other people?
The Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition (DSM-5-TR)

The Diagnostic and Statistical Manual of Five (or more) symptoms to be present during
Mental Disorders, Fifth Edition, Text the same 2-week period and represent a
Revision (DSM-5-TR), symptom criteria change from previous functioning. The
symptoms must be present nearly every day.
for a major depressive episode require:

At least one of the symptoms is either (1) depressed mood or (2) anhedonia,
meaning loss of interest or pleasure.
DSM-5-TR diagnostic criteria for a major depressive episode
A. Five (or more) of the following symptoms have been present during the same two-week period and represent a change from previous
functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.
NOTE: Do not include symptoms that are clearly attributable to another medical condition.
1) Depressed mood most of the day, nearly every day, as indicated by either subjective report (eg, feels sad, empty, hopeless) or observations made
by others (eg, appears tearful). (NOTE: In children and adolescents, can be irritable mood.)
2) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account
or observation).
3) Significant weight loss when not dieting or weight gain (eg, a change of more than 5% of body weight in a month), or decrease or increase in
appetite nearly every day. (NOTE: In children, consider failure to make expected weight gain.)
4) Insomnia or hypersomnia nearly every day. 5) Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective
feelings of restlessness or being slowed down).
6) Fatigue or loss of energy nearly every day. 7) Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every
day (not merely self-reproach or guilt about being sick).
8) Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by their subjective account or as observed by others).
9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for
committing suicide.
B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
C. The episode is not attributable to the direct physiological effects of a substance or to another medical condition.
NOTE: Criteria A through C represent a major depressive episode.
NOTE: Responses to a significant loss (eg, bereavement, financial ruin, losses from a natural disaster, a serious medical illness or disability) may include the feelings of intense sadness,
rumination about the loss, insomnia, poor appetite, and weight loss noted in Criterion A, which may resemble a depressive episode. Although such symptoms may be understandable or
considered appropriate to the loss, the presence of a major depressive episode in addition to the normal response to a significant loss should also be carefully considered. This decision
inevitably requires the exercise of clinical judgement based on the individual's history and the cultural norms for the expression of distress in the context of loss.
D. The occurrence of the major depressive episode is not better explained by schizoaffective
disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified NOTE: This exclusion does not apply if all of the manic-like or hypomanic-like episodes are
and unspecified schizophrenia spectrum and other psychotic disorders. substance-induced or are attributable to the physiological effects of another medical condition.
E. There has never been a manic or hypomanic episode.
Specify: w/ anxious distress, mixed features, melancholic features, atypical features, psychotic features, catatonia, peripartum onset, seasonal pattern
Comorbidities Associated with MDD
Anxiety disorders (comorbid anxiety and depression, the symptom profile may be balanced, or either symptom can
predominate)

Alcohol-use disorders

Eating disorders

Schizophrenia

Schizophreniform disorder

Somatic symptom disorders

Approximately 5% to 10% of all patients with depression have a coexisting thyroid disorder
MANAGEMENT of MDD
• Remission is defined as a virtual absence of depressive symptoms or a PHQ-9
score of less than five.
• Alternatively, response is defined as a substantial reduction in symptoms. On the
PHQ-9, it is at least a 50% decrease in the score.
• In clinical trials, less than one-half of patients experience complete remission of
depressive symptoms with an initial course of antidepressant therapy across 4 to 6
weeks. Remission is important, though, because incomplete relief of symptoms may
increase the risk of relapse and further impairment.
• The mainstays of treatment are the use of antidepressants and/or psychotherapy. For
mild to moderate depression, either medication or psychotherapy is recommended; if
the depression is more severe, evidence-based guidelines support the simultaneous
use of both.
• If a patient expresses suicidal intent or plan or has a history of suicidal attempts,
referral to a specialty provider is recommended
Pharmacological Management of MDD

Pharmacological therapy in patients with MDD may require several trials to

find the right medication. Agents that are effective in front-line treatment of
MDD are selective serotonin reuptake inhibitors (SSRIs); serotonin-
norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants (TCAs);
and bupropion (Wellbutrin), which is a norepinephrine dopamine reuptake
inhibitor, among others (Michigan Quality Improvement Consortium, 2016).
Considerations in Prescribing
Some antidepressants, such as bupropion, are contraindicated for people with
bulimia, and some drugs, such as paroxetine (Paxil), fluoxetine (Prozac), and
fluvoxamine (Luvox), have significant liver cytochrome (CYP) P450 interaction effects.
In older adults, antidepressants should be started at lower doses and titrated slowly.
For some pregnant women, antidepressants are a safer option than untreated
depression.
For breastfeeding mothers, sertraline (Zoloft) and paroxetine have demonstrated
undetectable serum levels in infants with no short-term effects, although further
research is needed on the long-term effects.
TCAs are not less effective than newer antidepressant medications, but they can
produce more side effects and have greater lethality in overdose.
Depression in adults: Antidepressant doses*
Usual total
starting dose per Usual total dose per day Extreme daily dose range
Drug
day (mg) (mg)¶
(mg)¶
Selective serotonin reuptake inhibitors
Citalopram 20 20 to 40Δ 10 to 40Δ
Escitalopram 10 10 to 20 5 to 30
Fluoxetine 20 20 to 60 10 to 80
Fluvoxamine 50 100 to 200 25 to 300
Fluvoxamine CR 100 100 to 200 100 to 300
Paroxetine 20 20 to 40 10 to 50
Paroxetine CR 25 25 to 50 12.5 to 62.5
Sertraline 50 50 to 200 25 to 300
Serotonin-norepinephrine reuptake inhibitors
Desvenlafaxine 25 to 50 50 to 100 50 to 400◊
Duloxetine (Cymbalta) 30 to 60 60 30 to 120§
Levomilnacipran 20 40 to 80 20 to 120
Milnacipran 12.5 100 to 200 50 to 300
Venlafaxine 37.5 to 75 75 to 375 75 to 375
Venlafaxine XR 37.5 to 75 75 to 225 75 to 375
Depression in adults: Antidepressant doses*
Usual total
Usual total dose per
starting dose per Extreme daily dose range
Drug day
day (mg)¶
(mg)
(mg)¶
Atypical agents
Agomelatine¥ (not available in
25 25 to 50 25 to 50
United States)
300 (maximum single
Bupropion 200 100 to 450
dose 150 mg)
300 (maximum single
Bupropion SR 12 hour 150 150 to 400
dose 200 mg)
150 to 450 (United States)
Bupropion XL 24 hour 150 300
150 to 300 (Europe)
Bupropion hydrobromide 24 hour 174 348 174 to 522
Mirtazapine 15 15 to 45 7.5 to 60
Serotonin modulators
Trazodone 100 200 to 400 100 to 600
Vilazodone 10 40 10 to 40
Vortioxetine 10 20 5 to 20

Useful w/ concomitant anxiety and depression when

SRIs/buspirone & SRI/gabapentin have not worked
Depression in adults: Antidepressant doses*
Usual total
Usual total dose per
starting dose per Extreme daily dose range
Drug day
day (mg)¶
(mg)
(mg)¶
Tricyclics and tetracyclics‡
Amitriptyline 25 150 to 300 10 to 300
Amoxapine 25 200 to 300 25 to 400
Clomipramine 25 100 to 250 25 to 300
Desipramine 25 150 to 300 25 to 300
Doxepin 25 100 to 300 10 to 300
Imipramine 25 150 to 300 10 to 300
Maprotiline 25 100 to 225 25 to 225
Nortriptyline 25 50 to 150 10 to 200
Protriptyline 10 15 to 60 5 to 60
Trimipramine 25 150 to 300 25 to 300
Monoamine oxidase inhibitors‡
Isocarboxazid 10 10 to 40 10 to 60
Phenelzine 15 15 to 90 7.5 to 90
6 mg/24 hour 6 to 12 mg/24 hour
Selegiline transdermal 6 to 12 mg/24 hour patch
patch patch
Tranylcypromine 10 30 to 60 10 to 60
 Pharmacology of medicines for treatment of adults
with MDD and chronic pain
Effect on
Initial daily Daily oral dose Selected characteristics relevant to treatment
Drug Primary metabolism ¶
metabolism of
oral dose* range* of adults with GAD
other drugs¶
SSRI antidepressants
Applies to all SSRIs: Onset of effect may be delayed 2 to 4 weeks or more. Adverse effects among the SSRIs include: Nausea, diarrhea,
insomnia/agitation, somnolence, impaired sexual function, and hyponatremia. Adverse effects of individual agents are presented in a separate table in
UpToDate.
•Lower risk of insomnia/agitation
•Few drug interactions
Citalopram 10 mg 10 to 40 mg CYP3A4, 2C19 None
•Can prolong QT interval with increasing blood
levels
•Greater risk of insomnia/agitation
Limited (minor CYP2C9,
Sertraline 25 to 50 mg 50 to 200 mg None •More frequent diarrhea and other gastrointestinal
2D6, and 3A4)
complaints
TCAs
older class of antidepressants that are also used in the treatment of chronic pain, particularly neuropathic pain; work by inhibiting the reuptake of
serotonin and norepinephrine, and they also have analgesic properties that can help reduce pain intensity.

Amitriptyline 25 mg 150 – 300 mg •Frequently used off-label for chronic pain

conditions such as neuropathy, fibromyalgia, and
migraine prophylaxis. It can also improve sleep
Nortriptyline 25 mg 50 – 150 mg quality.
 Effect on
Initial daily Daily oral dose Primary Selected characteristics relevant to treatment of
Drug metabolism of
oral dose* range* metabolism¶ adults with GAD
other drugs¶
SNRI antidepressants
Onset of effect and adverse effects of the SNRIs are similar to the SSRIs (refer to above). Adverse effects of individual agents are presented in a
separate table in UpToDate.
•Greater risk of insomnia/agitation
•Useful for treatment of comorbid painful conditions
Duloxetine CYP1A2, Inhibits •Withdrawal symptoms if not tapered
30 mg 60 to 120 mg
(Cymbalta) 2D6 CYP2D6 •FDA-approved for the treatment of both major depressive disorder
and chronic pain conditions such as diabetic neuropathy,
fibromyalgia, and chronic musculoskeletal pain
•Greater risk of insomnia/agitation
•Increased blood pressure (primarily diastolic) and heart rate with
Venlafaxine (Effexor) CYP2D6, increasing doses
75 mg 75 to 225 mg None
(extended-release) 3A4 •Useful for treatment of comorbid painful conditions
•Few drug interactions
•Withdrawal symptoms if not tapered
Atypical: Atypical antipsychotics work by modulating dopamine and serotonin neurotransmission, and they may have additional analgesic
properties that contribute to pain relief.
•May be used adjunctively for depression and has shown some efficacy in chronic pain management, especially in conditions like
Aripiprazole (Abilify) fibromyalgia

•Off-label use for depression and may provide mild analgesic effects in certain chronic pain conditions.

Quetiapine •An SGA

•Potential augmentation choice for partial response to antidepressant or alternate as monotherapy
25 – 50 mg 50 – 30 mg CYP3A4 None •Sedation, extrapyramidal effects, weight gain, and metabolic side effects (refer to separate table on SGA adverse effects)
(Seroquel) •Rarely tardive dyskinesia

Dependent •A GABA analog calcium-channel modulator antiseizure medication

300 to 2400 mg on renal •Onset within days of starting treatment
Gabapentin 300 mg None
in divided doses function for •Sedation and dizziness
clearance •Tolerance, dependence, and withdrawal possible
 Effect on
Initial daily Daily oral Primary metabolism Selected characteristics relevant to treatment of adults with
Drug
oral dose* dose range* metabolism¶ of other GAD
drugs ¶

•An atypical antidepressant

CYP1A2, 2D6,
Mirtazapine 15 mg 15 to 60 mg None •Alternate or augmentation choice for anxiety with insomnia
3A4
•Sedating; notably increases appetite
•An SGA
•Potential augmentation choice for partial response to
antidepressant or alternate as monotherapy
Quetiapine 25 to 50 mg 50 to 300 mg CYP3A4 None
•Sedation, extrapyramidal effects, weight gain, and metabolic side
effects (refer to separate table on SGA adverse effects)
•Rarely tardive dyskinesia
25 to 50 mg
•A sedating antihistamine with anxiolytic properties
50 mg at three to four
Hydroxyzine None None •Augmentation option for treatment of insomnia
bedtime times per day
•Anticholinergic side-effects with increasing doses
as needed
•A tricyclic antidepressant
75 to 200 mg •Anticholinergic side effects
75 mg in
Imipramine in divided CYP2C19, 2D6 None •Cardiotoxic in overdose
divided doses
doses •May be poorly tolerated relative to SSRI and SNRI
antidepressants

•A GABA analog calcium-channel modulator antiseizure

medication
•Onset within days of starting treatment
50 to 300 mg Dependent on •Approved for treatment of anxiety in some countries (not United
50 mg in
Pregabalin in divided renal function for None States)
divided doses
doses clearance •Sedation and dizziness
•Tolerance, dependence, and withdrawal possible
•Schedule V controlled substance in United States
•Many patients require >150 mg/day, up to 300 mg/day
GAD: generalized anxiety disorder; SRI: serotonin reuptake inhibitor; CBT:
cognitive-behavioral therapy; SSRI: selective serotonin reuptake inhibitor; SNRI:
serotonin-norepinephrine reuptake inhibitor; EPS: extrapyramidal side effects.
* Augmentation with psychotherapy (ie, CBT) can be done at any point in the
algorithm.
¶ SRI includes both SSRIs and SNRIs.
Δ Adequate trial is considered to be 6 weeks at therapeutic dose range for
medication.
◊ Our first line for augmentation is buspirone; however, in individuals with
significant mood fluctuation, irritability, or in those with diagnosis of bipolar
disorder (with mania or hypomania), valproic acid or lamotrigine are acceptable
alternatives.
§ We typically try augmentation with two different agents at therapeutic range for
4 weeks before considering the individual to not have acceptable response to
augmentation efforts.
¥ Choice of antidepressant is based on symptoms present and potential side
effects of medications. In individuals with decreased appetite or insomnia, we
would use mirtazapine. In individuals sensitive to weight gain, we would use
vilazodone.
‡ For individuals with current unhealthy alcohol or substance use we address
these concerns prior to treating generalized anxiety. In some cases, such as low-
risk use of alcohol, we address them concurrently.
† For individuals starting an antipsychotic medication, we monitor for EPS,
prolonged QTc, and metabolic dysregulation. Refer to content in UpToDate.
** Benzodiazepines can be used as monotherapy in individuals who have not
responded to any prior agents or as an adjunctive agent based on response to
prior agent. Refer to UpToDate content.
Common to most SSRIs:
Response rates: 60%–70% SSRI-induced mania in BD patients
Remission rates: 20%–35% If anxiety/panic disorder develops or
patient has a history of these disorders,
Safest class of antidepressants in overdose start low and adjust dose slowly.
Avoid sudden discontinuation
due to possible withdrawal Increased risk of suicidal behavior in
syndrome. Do not prescribe children, adolescents, and young adults
with MAOIs due to risk of
serotonin syndrome. Absent or slight weight gain except for
Agitation, dizziness, headache, drowsiness (dose in paroxetine
evening), insomnia (dose in morning), nausea/vomiting
(self-limiting 1–3 weeks), and xerostomia SIADH, risk Sexual dysfunction in 30%–40%, resolving
is highest in older adults after medication is discontinued
Wait 2 weeks after discontinuing an SSRI
Serotonin syndrome (caution with “triptans” or sleep to start an MAOI (wait 5 weeks after
aids) fluoxetine is discontinued). Wait 2 weeks
after discontinuing an MAOI to start an
SSRI.
Common to most SNRIs:
Response rates: 60%–70%
Remission rates: up to 50% SNRI-induced mania in BD
If anxiety/panic disorder develops or if the patient
Safety in overdose is intermediate, has a history of these disorders, start low and adjust
between SSRIs and TCAs. Avoid dose slowly. Contraindicated in uncontrolled closed-
sudden discontinuation angle glaucoma

Do not prescribe with MAOIs Sexual dysfunction, resolving in days after

Agitation, weakness, dizziness, headache, medication discontinuation
drowsiness, insomnia, nausea/vomiting (self-limiting
1–3 weeks), and xerostomia Increased risk of suicidal Monitor blood pressure for diastolic hypertension.
behavior in children, adolescents, and young adults Wait 2 weeks after discontinuing
an SNRI to start an MAOI. Wait 2
SIADH, risk is highest in older adults weeks after discontinuing an MAOI
to start SNRI
Serotonin syndrome (caution with “triptans”)
Considerations in prescribing
• Bupropion is contraindicated in people with bulimia
• Paroxetine (Paxil), fluoxetine (Prozac), and fluvoxamine (Luvox)
have significant liver CYP 450 interaction effects
• In older adults, antidepressants should be started at lower
doses and titrated slowly
• For some pregnant women, antidepressants are safer than
untreated depression
• Breastfeeding: sertraline (Zoloft) and paroxetine have
undetectable levels in infants with no short-term effects
• TCAs are not less effective than newer antidepressant
medications but they can produce more side effects and have
greater lethality in overdose
Follow-Up

Ensure adherence to therapy.

Treatment outcome should be assessed regularly, using formal diagnostic

assessment tools.

Target symptoms are used to evaluate the effectiveness of medication during

early stages of treatment and until full symptom remission is obtained.

In moderate to severe depression, follow-up is determined by the severity of the

initial PHQ-9.
Follow-Up
reasonable criterion for extending the initial treatment is to assess whether the patient is experiencing a 50% or greater reduction in
baseline symptom severity at 6 weeks of the therapeutic dose
• If the patient’s symptoms are reduced by 50% or more, but the patient is not yet at remission, and if medication has been well
tolerated, continue to prescribe and continue to raise the dosage.

• In the acute phase of treatment and recovery, the patient should be seen or contacted every 1 to 2 weeks within the first
month of therapy and at least once in the succeeding 4 to 8 weeks.

• For patients who can be treated effectively with antidepressant medication, satisfactory symptom relief often is achieved
within 4 to 6 weeks. Many patients begin to feel better in 2 to 3 weeks.
• The duration of medication treatment for uncomplicated MDD is at a minimum 6 to 12 months at the treatment dose
(Michigan Quality Improvement Consortium, 2016). A longer treatment period is recommended for patients with complicated
or multiple disorders or patients who have a history of one or more years of untreated depression. In these instances,
treatment duration should extend from 15 months to an indefinite time.
• When the patient reports target symptom relief or when the assessment indicates symptom remission has been achieved,
the practitioner and patient develop a treatment and discontinuation plan. Short half-life antidepressants are discontinued
gradually over a period of 2 to 3 weeks. People who experience significant discontinuation symptoms may report flu-like
symptoms that last a few days.
• Consultation with a specialist should be considered if the patient has failed two medications after adequate trials and dosing.
Consultation can also be sought if discontinuation symptoms appear to be significant or persistent.
Discontinuation of Medication

Short half-life antidepressants are discontinued gradually over a

period of 2 to 3 weeks. People who experience significant
discontinuation symptoms may report flu- like symptoms that last
a few days.

SNRIs should be titrated down even slower

Indications for Referral

Consider if the patient

Consider if several
has failed two
comorbidities or
medications after
unfavorable of
adequate trials and
unpredictable response
dosing. Suicidal
to treatment.
Ideation, Suicidal Plan.

Put patient on treatment and have manic episode  indication for referral