Depression Flashcards
Which psychiatric disorder is highly associated with suicide?
- Schizophrenia (46.3%)
- Depression (26.8%)
What are the 3 best predictors of suicide?
- Hx of attempted suicide using highly lethal means
- Coexisting significant physical illness
- Delusions
Components of suicide risk assessment:
- Rapport
- Collateral information (w consent)
- Suicide inquiry (ideation, suicide plan, intent, explore ambivalence)
- Consultation with specialist when in doubt
Suicide risk management
- Identify and manage underlying disorders (e.g., depression)
- Identify risk factors
- Prior attempts
- Past/current psychiatric disorders
- Key symptoms: anhedonia, hopelessness, anxiety, impulsivity, aggression, delusions
- FH of suicide, child maltreatment
- Stressors: triggering events
- Access to meds (drug overdose), firearms, other lethal means
- Identify protective factors
- Removing means
- Activating support system
Suicide questions to ask:
Most impt to ask: Have you had any thoughts of killing yourself?
- refer to counseling
Additional questions: to seek IMMEDIATE help (emergency room)
- Have you had intention of acting on them?
- Have you started to work out details on how to kill yourself?
- Have you done anything / prepared to do anything to end your life? Was this within the past 3 months?
Etiology of major depressive disorder
- Biological (neuroendocrine)
- Hormonal influences (incr secretion of cortisol, major stress hormone)
- Monoamine hypothesis (dcr neurotransmitter in the brain - Norepinephrine, Serotonin, Dopamine)
- Psychological
- Loss, negative self-esteem
- Psychosocial
- Isolation, loss of social support
- Genetics
- S/S genotype on SERT gene: more vulnerable to depression of early life stress
- L/L genotype more immune to depressive effects of early life trauma
- Medical disorders
- Pharmacological (intoxication, withdrawal)
Secondary causes for depression: Medical disorders
- Endocrine disorders (Hypothyroidism, Cushing syndrome, Diabetes)
- Deficiency states (Anemia)
- Infections - can cause dysphoric mood
- Metabolic disorders (electrolyte imbalance, hepatic encephalopathy)
- Cardiovascular: CAD, CHF, MI
- Neurological: Alzheimer’s, Epilepsy, Parkinson’s, post-stroke, pain - frustration, depression
- Malignancy, cancer
Secondary causes for depression: Psychiatric disorders
- Alcoholism
- Anxiety disorders
- Eating disorders
- Schizophrenia
Secondary causes for depression: Drug-induced
- Lipid-soluble beta-blockers (*propranolol can cause psychosis)
- Psychotropics: CNS depressants (BZD, opioids, barbiturates), anticonvulsants, tetrabenazine
- Withdrawal from alcohol, stimulants**
- Systemic corticosteroids (can cause anxiety, psychosis, depression)
- Isotretinoin (Vit A)
- Interferon-B-1a (Hep C tx)
DSM-5 Criteria
(In SAD CAGES)
A) At least 5 out of 9 symptoms (including depressed mood or loss of interest) over the most of the same 2 weeks, causing significant distress or functional impairment)
- Loss of interest
- Sleep: insomnia
- Appetite: LOA, weight loss
- Depressed mood
- Concentration: impaired concentration and decision making
- Activity: psychomotor retardation or agitation (retardation: slowed speech, decreased movement, and impaired cognitive function) (agitation: restlessness and anxiety, repetitive and unintentional movements)
- Guilt
- Energy: dcr energy, fatigue
- Suicidal: thoughts or attempts
B) Symptoms cause significant distress or impairment
C) Symptoms NOT caused by underlying medical conditions or substance
What is the 1st line treatment for MDD?
Mild depression - psychosocial treatments
Mod-severe depression - psychosocial + pharmacological treatments
What is persistent depressive disorder (dysthymia)?
If patient has depressed mood + 2 or more symptoms, for 2 years, but does not fulfill MDD diagnosis
- May be treated with antidepressants as well
What are 2 differential diagnosis for MDD?
- Adjustment disorder
- Symptoms occur within 3 months of onset of a stressor, but once stressor is terminated, symptoms do not persist for additional 6 months
- Acute stress disorder
- Symptoms occur within 1 month of a traumatic event and last 3 days to 1 month (if prolong >1m: PTSD)
- Symptoms include: intense fear, helplessness, horror, dissociation, re-experiencing, avoidance, increased arousal
These disorders are NOT to be treated with antidepressants, they can be treated with benzodiazepines instead
General assessments
- History of present illness
- Psychiatric history – history of manic/hypomanic episodes - bipolar depression cannot use antidepressants
- Substance use – cigarettes, alcohol, substances
- Complete medical history and medication history (Drug allergy? Other medications? Compliance?)
- Family, social, forensic, developmental, and occupational history (1st-degree FH of illness, treatment, and response; review psychosocial circumstances every visit)
- Physical and neurological exam (Injury? Esp head trauma?)
- Mental state exam (Suicidal, homicidal ideations and risks; Reassess MSE every interview to evaluate efficacy and tolerability)
- Labs and other investigations - Vital signs (BP, O2), weight, BMI, FBC, urea, electrolyte, creatinine, LFTs, TFTs, ECG, FBG, lipid panel, urine toxicology
FBC: rule out anemia, infection
TFTs: rule out hypothyroidism - depressed mood
ECG, CVD: cardiovascular events and depression
Exclude general medical conditions or substance-induced/withdrawal symptoms (e.g., psychosis, depression, mania, anxiety, insomnia)
Compare the onset, consciousness, memory b/w Depression, Delirium, Dementia, and Withdrawal/intoxication
ONSET:
- Depression: cyclical (worse when there’s a stressor)
- Delirium: Acute
- Dementia: Insidious, progressive
- Withdrawal/intoxication: Acute
Consciousness
- Depression: Generally unimpaired
- Delirium: Impaired
- Dementia: Clear until later stages
- Withdrawal/intoxication: Continuum of unimpaired to impaired
Memory
- Depression: Intact
- Delirium: Poor
- Dementia: Poor short and long-term memory
- Withdrawal/intoxication: Intact
Psychiatric rating scales
Clinician Rated: Hamilton rating scale for depression (HAM-D) to evaluate recovery GOLD STANDARD
- Therapy goal: symptom-free
- Remission =<7
- Response = 50% improvement
Self-rated screening/assessment tool: PHQ-9 / PHQ-2
- Score 1-4: minimal symptoms (in remission)
- Score 5-9: mild depression
- Score 10-14: mod depression
- Score 15-19: mod-severe depression
- Score >=20: severe depression
10 and above: warrants starting of antidepressants
PHQ2
Over the past two weeks, how often have you been bothered by any of the following problems?
- Little interest or pleasure in doing things
- Feeling down, depressed, or hopeless
VS PHQ9 - basically all 9 symptoms of In SAD CAGES
Goals of treatment in MDD
- Remission of symptoms (symptom-free)
- Treatment adherence
- Suicide prevention
Non-pharmacological therapy in MDD
- Sleep hygiene
- Psychotherapy (1st line for mild depression, includes coping mechanisms; not suitable as monotherapy for mod-severe MDD)
- Counseling
- Neurostimulation (reserved for severe/refractory depression) - Electroconvulsive treatment (ECT), rTMS
- Light therapy - for seasonal affective disorder
What classes do the following drugs belong to?
- Amitriptyline
- Vortioxetine
- Moclobemide
- Clomipramine
- Fluoxetine
- Mirtazapine
- Venlafaxine
- Bupropion
- Duloxetine
- Agomelatine
- Fluvoxamine
- Escitalopram
- Trazodone
- Ketamine
- TCAs: Amitriptyline, Clomipramine
- SSRIs: Fluoxetine, Fluvoxamine, Escitalopram
- SNRIs: Venlafaxine, Duloxetine
- SMS: Vortioxetine
- NaSSA: Mirtazapine (antagonist of the a2 autoreceptors)
- RIMA (reversible MAOi): Moclobemide
- NDRI: Bupropion
- Melatonin receptor agonist (act on MT1 and MT2 receptors, indirectly increases NA and dopamine): Agomelatine
- SARI: Trazodone
- Glutamate NMDA receptor (calcium ion channel) antagonist: Ketamine (anesthetic)
Which antidepressant has the fastest oral onset?
Mirtazapine
- works directly on autoreceptors to incr neurotransmitter release, does not inhibit reuptake of neurotransmitters (within 1 week)
Oral Escitalopram also has quick onset as it is very potent (within 1 week)
FYI:
- Onset of IV ketamine within 1h
- Onset of ECT within 1min
All SSRI are in SDL except:
Paroxetine and Escitalopram
*Also note that bupropion is NOT subsidized
Common indications for antidepressants
- TCAs
*Dose for amitriptyline, clomipramine
Besides depression,
Amitriptyline (30-300mg/day, max dose 300mg/day) - neuropathic pain, migraine prophylaxis
Clomipramine (max dose 300mg/day) - OCD (2nd line), Cataplexy a/w narcolepsy
Nortriptyline - neuropathic pain
Imipramine
Dothiepin
Common indications for antidepressants
- SSRIs
*Dose for fluoxetine
Besides depression, used for anxiety disorders due to its serotonergic properties
Fluoxetine (20-60mg OM, max 80mg): OCD
Fluvoxamine: OCD
Escitalopram: Anxiety disorders
Citalopram: Panic disorders
Paroxetine: Anxiety disorders
Sertraline: OCD, Panic disorder
Common indications for antidepressants
- SNRI
Besides depression,
Venlafaxine: GAD, PD
Duloxetine: GAD, chronic musculoskeletal pain, diabetic neuropathy, stress urinary incontinence, fibromyalgia
*Venlafaxine has similar structure to tramadol
Common indications for antidepressants
- RIMA: Moclobemide
Besides depression,
Moclobemide: Social anxiety disorder
Common indications for antidepressants
- NDRI: Bupropion
Besides depression,
Buproprion can be used for smoking cessation (increases NA and dopamine at ventral tegmental area)
Common indications for antidepressants
- SARI: Trazodone
Not typically used as an antidepressant as antidepressant dose of 300-600mg per day is too sedating, not tolerable
May use off-label for insomnia, commonly use PO 25mg at bedtime PRN for insomnia
It is also anti-hypertensive
NaSSA: Mirtazapine dose
15-45mg/day, max dose 45mg/day
Why are TCAs not the first line DOC for depression?
TCA - a/w many adverse events
Antidepressant effects via:
- Norepinephrine reuptake
- Serotonin reuptake
ADRs:
- Sedation, weight gain
- H1 histamine receptor antagonism (however, tolerance to sedation can develop in 1-2 weeks)
- Postural hypotension
- a1-adrenoceptor sympathetic block
- Dry mouth, blurred vision, constipation/urinary retention
- Muscarinic receptor antagonism
Also:
- GI effects (N/V/D) (5-HT3 agonism)
- Sexual dysfunction (5-HT2 agonism)
- Seizures due to proconvulsant properties of TCAs
- Conductance abnormalities - arrhythmias, ECG changes
- Fatal on overdose
PK Characteristics of Fluoxetine
Fluoxetine
- Half-life: 4-6 days
- Active metabolite: Norfluoxetine (half-life: 4-16 days)
PK Characteristics of Vortioxetine
Vortioxetine
- Half-life: 66 hours (in circulation for ~2.75days)
PK Characteristics of Bupropion
Bupropion
Metabolites:
- 3 amphetamine-like metabolites
- Increases alertness and increases NA activation: may cause insomnia
Dosing:
- Therefore, always dosed in the day instead of night
- 1st and 2nd dose should be spaced 8h apart
Half-life:
- Half-life: 10-21h
- due to short half-life, sustained release formulation is used (swallow whole, do not crush)
Bupropion is suitable for patients with no energy/feel sleepy as it is a stimulating antidepressant
PK Characteristics of Sertraline (SSRI)
Sertraline
- Bioavailability 36%, increases by 30-40% with food intake
- Counseling point: Sertraline take with food to increase absorption
General side effects of serotonergic agents (SSRI/SNRI/TCA/SMS/SARI)
GI - N/V/D [5HT3 agonism]
Sexual dysfunction [5HT2 agonism]
Side effects of TCA
GI - N/V/D [5HT3 agonism]
Sexual dysfunction [5HT2 agonism]
Anticholinergic [M1 antagonism]
Sedation, weight gain [H1 antagonism]
Orthostatic hypotension [a1 antagonism]
Arrhythmias, ECG changes [conductance abnormalities]
Seizures [proconvulsant]
Fatal on overdose
Side effects of SSRI
Note that the SEs of SSRI are seen in other serotonergic agents as well
GI - N/V/D [5HT3 agonism]
Sexual dysfunction [5HT2 agonist]
Headache, transient nervousness during initiation
Fluoxetine: Insomnia
Paroxetine: most anticholinergic, sedating, weight gain, withdrawal (short half-life), avoid in elderly
Escitalopram/Citalopram: ECG changes - QTc prolongation if high dose used in elderly => can result in sudden cardiac death, TDP
Others:
Hyponatremia (SIADH)
Bleeding risk (esp with concurrent antiplatelet/anticoagulant)
EPSE
Side effects of Venlafaxine (SNRI)
GI - N/V/D [5HT3 agonism]
Sexual dysfunction [5HT2 agonism]
Due to increase NE,
- causes or worsens hypertension (incr BP)
- worsen anxiety, agitation (at least initially)
- worsen LOA (not first choice if pt has loss of appetite)
Side effects of Duloxetine (SNRI)
GI - N/V/D [5HT3 agonism]
Sexual dysfunction [5HT2 agonism]
Urinary hesitation (rmb it can be used to treat stress urinary incontinence)
Due to increase NE,
- worsen anxiety, agitation (at least initially)
- worsen LOA (not first choice if pt has loss of appetite)
Side effects of Mirtazapine (a2-adrenoceptor antagonist, increases serotonin and NE)
Somnolence (beneficial for pt with insomnia) [H1 antagonism]
Increase appetite, weight gain (beneficial in pt with LOA) => *Need to monitor FBG, HbA1c, lipids
Reverse GI and sexual side effects of SSRI/SNRI [5HT3 and 5HT2 antagonism]
Mirtazapine is a sedating and appetite stimulating antidepressant; may monitor FBG/HbA1c and lipids annually
Side effects of Bupropion
*Bupropion (NDRI) blocks reuptake of NE and dopamine, no serotonergic effects
*Also state which group of patients Bupropion is contraindicated in
Think about amphetamine like metabolites
Seizure
Insomnia
Anxiety
Psychosis
(Not suitable for hx of seizure, psychosis, eating disorder)
Decrease sexual effects of SSRI/SNRI since no serotonergic effect
Contraindicated with pt with eating disorder
- poor eating can increase risk of seizure
Due to increase NE,
- worsen anxiety, agitation (at least initially)
- worsen LOA (not first choice if pt has loss of appetite)
Bupropion may be a suitable choice for pt with no energy, sleepy
Side effect of MAOi
Hypertensive crisis (due to accumulation of tyramine)
- Less in reversible (RIMA) Moclobemide
Side effect of Trazodone
GI - N/V/D [5HT3 agonism]
Sexual dysfunction [5HT2 agonism]
Sedation [H1 antagonism]
Orthostatic hypotension [a1 adrenoceptor antagonism]
Rare: priapism
Side effect of Agomelatine
MT1 agonist, MT2 agonist, 5HT2C antagonist (incr DA, incr NE)
GI SEs
Increase LFTs, risk of transaminitis (incr risk with CYP1A2 inhibitors)
Less sexual dysfunction
Contraindicated with Fluvoxamine and Ciprofloxacin (CYP1A2 inhibitors) as it is a CYP1A2 substrate
Suicidality risk with antidepressants
- who should be counseled?
Suicidality association in patients =<24y, mandatory counseling required
What adjunctive treatments may be used in MDD?
- Second-generation antipsychotics (SGAs)
- Short-course of PRN hypnotics/anxiolytics (help sleep/relax)
Adjunctive treatment: SGA
- Which drugs?
- MOA
- SE
Aripiprazole, Brexpiprazole, Quetiapine
MOA:
- 5-HT1A partial agonism: anxiolytic effects
- 5-HT2A antagonism: antidepressant effects, improve negative symptoms
=> improve mood
SE:
- EPSE (Aripiprazole, Brexpiprazole)
- Metabolic SE (Quetiapine)
Adjunctive treatment: Esketamine (Spravato IN)
- MOA
- SE
MOA: NMDA receptor antagonist
SE: headache, dissociation, confusion, dizziness, hallucination, nausea, sedation, anxiety, increase BP
Use as: Adjunct to SSRI/SNRI for TRD
Adjunctive treatment: PRN Hypnotics (help sleep/relax)
- Which drugs?
- MOA
- SE
- Benzodiazepines
- MOA: potentiates GABA
- SE: drowsiness, weakness, amnesia, dependence
- Z-hypnotics
- MOA: preferentially binds to BZD-binding sites with y and a1 subunits (thus causing sedation)
- SE: Taste disturbance (Zopiclone), complex sleep behaviors (sleep-walking), dependence
- Antihistamines
- SE: Drowsiness, anticholinergic SE, constipation
Complementary and Alternative Medicines
- Therapeutic lifestyle/behavioral change
- Nutritional
- Avoid
- Therapeutic lifestyle/behavioral changes
- Sleep hygiene
- Exercise
- Relaxation techniques
Nutritional
- Vit B12
- L-methylfolate
- Vit D
- Omega-3 fatty acids
AVOID:
- St John Wort (significant DDI with antidepressant as it is an inducer, do not use concomitantly)
Pharmacological Management of MDD
Describe:
- Indication:
- Choice:
- 1st line:
- Efficacy:
Antidepressants
- Indication: mod-severe MDD, certain anxiety disorders, dysthymia (*NOT used in bipolar)
- Choice: Selection based on target symptoms, comorbid conditions, DDIs, prior response, patient preference
- 1st line monotherapy: Mirtazapine, SSRI, SNRI, Bupropion, Agomelatine > TCA > MAOi
- Efficacy: response rate 50%, remission rate 30% with first antidepressant; ALL antidepressants have similar efficacy for uncomplicated first episode of MDD
ACUTE phase treatment of MDD
- Adequate trial
- Onset
- Time course of treatment response
Adequate trial = adequate dose + duration (4-8weeks)
Onset:
- Delayed onset of effectiveness due to gradual downregulation of presynaptic autoreceptors in the synapse
- (e.g., SSRI Fluvoxamine inhibits serotonin uptake within 1h, but mood symptoms only improve after 1-2months)
Time course of treatment response:
- Physical symptoms may improve in 1-2 weeks (insomnia, LOA)
- Mood symptoms may take longer 4-8 weeks
CONTINUATION phase treatment of MDD
- How long more to continue treatment?
1st episode of uncomplicated MDD: continue for at least another 4-9months
What is the total treatment duration for MDD?
Total (acute + continuation) = at least 6-12months
If patient stops treatment early, likelihood of recurrence is high
Treatment approach: No Response
When and how to switch antidepressant?
- When to switch
- Cross titration
- Direct switch
- Switching from serotonergic antidepressant to non-serotonergic agent
- Wash out for MAOi
- Switch when completely ineffective/intolerable to adequate dose in 2-4 weeks (however if there’s response than adequate trial is 4-8 weeks; if some response may increase dose to max)
- If cross-titration: watch for serotonin syndrome if serotonergic agents
- If direct switch: one SSRI can be stopped totally and the next serotonergic agent initiated
- If switching from serotonergic antidepressant used daily for the past 2 months to non-serotonergic agent:
=> gradual cross-tapering over several weeks can reduce risk of antidepressant discontinuation syndrome
- Wash out period necessary for MAOIs (so as to avoid serotonergic syndrome)
=> Moclobemide to another antidepressant: 24h washout
=> Another antidepressant to Moclobemide: washout at least 1 week (5 week if stopping Fluoxetine)
Treatment approach: Partial Response
Augmentation
Combine a 2nd antidepressant (with diff MOA) to the existing antidepressant that has a partial response
- E.g., add Mirtazapine, Bupropion-SR, Lithium, Adjunctive SGAs (Quetiapine, Aripiprazole, Brexpiprazole)
Treatment approach: treatment resistant depression
- Define TRD
- Tx approach for TRD
TRD: no response to 2 or more adequate trials (4-8 weeks) of antidepressants
Treatment:
- Neurostimulation: ECT, rTMS
- Symbyax (Olanzapine 6mg + Fluoxetine 25mg) capsule
- Spravato nasal spray (Esketamine), adjunct to SSRI/SNRI
Antidepressant discontinuation syndrome
(*NOT withdrawal)
- Which antidepressants more likely to produce discontinuation syndrome?
- What are the symptoms?
- Onset
- Duration
- Resolve
Worse with abrupt stopping of a regular treatment, esp antidepressants with short half-life: e.g., Paroxetine, Venlafaxine
Symptoms: (*NOT deadly, no need A&E)
(FINISH)
- Flu-like symptoms (lethargy, fatigue, headache, achiness, sweating)
- Insomnia (w vivid dreams, nightmares)
- Nausea (sometimes vomiting)
- Imbalance (dizziness, vertigo, light-headedness)
- Sensory disturbances (burning, tingling, electric-like sensations)
- Hyperarousal (anxiety, irritability, agitation, aggression, mania)
Onset
- 36-72h
Duration:
- 3-7 days
Resolve:
- Typically resolve without treatment over 1-2 weeks
Antidepressant discontinuation syndrome
- How to avoid?
- Which antidepressants may not need?
Gradually taper dose (by half tablet of lowest strength every 1-2 weeks) if pt had been on regular dosing for more than 6-8 weeks
Fluoxetine, Bupropion have long half-life, no need for gradual tapering of dose
Antidepressant-induced mania
- Mechanism
- Onset
Mechanism is unknown: incr in NE and Dopamine transmission
Fast onset: initial few days to 2 weeks (as fast as 3 days)
Use of antidepressant increases the risk of developing mania/bipolar disorder (diagnosis: bipolar depression rather than MDD)
[Medical comorbidities and DOC]
BPH, narrow angle glaucoma
Avoid TCA and Paroxetine (due to anticholinergic effects - antagonist of M1)
[Medical comorbidities and DOC]
- Underweight
Mirtazapine (incr appetite, incr weight gain)
[Medical comorbidities and DOC]
- Chronic pain/neuropathy
Duloxetine
[Medical comorbidities and DOC]
- Hypertension
Avoid TCAs, SNRIs => incr sympathetic tone, worsens HTN
Both inhibit the reuptake of norepinephrine, resulting in increase of sympathetic nervous system, which increases the HR, which contributes to increase in BP
Consider Sertraline
[Medical comorbidities and DOC]
- Cardiovascular disease
Consider Sertraline (antiplatelet effect)
Avoid TCA and Escitalopram => risk of ECG changes
[Medical comorbidities and DOC]
- Seizures
Avoid TCAs (proconvulsant), Bupropion
Consider SSRIs, SNRIs
[Medical comorbidities and DOC]
- Eating disorder
Consider Fluoxetine
Avoid Bupropion (contraindicated) => risk of seizures
Also avoid SNRIs such as Venlafaxine
[Medical comorbidities and DOC]
- Insomnia
Consider mirtazapine
Avoid Bupropion (amphetamine like metabolites, worsens insomnia)
Fluoxetine and Escitalopram also cause insomnia
[Medical comorbidities and DOC]
- Elderly
Avoid TCAs (anticholinergic + postural hypotension)
Avoid Paroxetine
Avoid Escitalopram at high doses (ECG changes esp in elderly)
Hyponatremia - a/w all antidepressants, esp SSRI (lower risk with Agomelatine, Mirtazapine, Bupropion)
[Medical comorbidities and DOC]
Tamoxifen therapy
(Tamoxifen is a CYP2D6 substrate that must be converted to active drug)
Consider: Venlafaxine/Desvenlafaxine, Escitalopram
Avoid CYP2D6 inhibitors: Paroxetine, Fluoxetine, Bupropion
[Medical comorbidities and DOC]
Pregnancy
Avoid Paroxetine and Bupropion
May consider Nortriptyline in late pregnancy
