MDD Flashcards
Suicide risk assessment
- Identifying & managing underlying disorders
- Identifying risk factors
- Identifying protective factors (or lack thereof)
- Removing means
- Activating support system
Suicide risk factors
a. Prior attempt
b. Past/current psychiatric disorder
c. Key symptoms: anhedonia, hopelessness, anxiety, impulsivity, aggression,
delusions
d. Family history (suicide, child maltreatment)
e. Stressors (humiliating events)
f. Access to medicine (overdose), firearms, pesticides, other lethal means
Columbia-Suicide Severity Rating Scale (C-SSRS) Q1
Have you wished you were dead or wished you could go to sleep and not wake up?
Columbia-Suicide Severity Rating Scale (C-SSRS) Q2
Have you had any actual thoughts of killing yourself?
Columbia-Suicide Severity Rating Scale (C-SSRS) Q3
Have you been thinking about (how) you might do this?
Columbia-Suicide Severity Rating Scale (C-SSRS) Q4
Have you had these thoughts and had some intention of acting on them?
Columbia-Suicide Severity Rating Scale (C-SSRS) Q5
Have you started to work out or have worked out the details of how to kill yourself?
Columbia-Suicide Severity Rating Scale (C-SSRS) Q6a
Have you done anything, or start to do anything, or prepared to do anything to end your life?
Columbia-Suicide Severity Rating Scale (C-SSRS) Q6b
If yes (to 6a), was this within the past 3 months?
Pathophysiology of MDD
- Hormonal influences: increase secretion of cortisol (major stress hormone)
- Monoamine hypothesis: decrease neurotransmitters in the brain (norepinephrine, serotonin, dopamine)
What was an important early evidence of monoamine theory?
Reserpine, which inhibits NE and 5-HT, depressed mood
Secondary causes for MDD
- Medical disorders
- Psychiatric disorder
- Drug-induced
What medical disorders can cause depression? (1)
Endocrine disorder: hypothyroidism, Cushing syndrome, T2DM (bidirectional association in women)
What medical disorders can cause depression? (2)
Deficiency states: anaemia, Werncikle’s encephalopathy
What medical disorders can cause depression? (3)
Infections: CNS infections, STD/HIV, TB
What medical disorders can cause depression? (4)
Metabolic disorders: electrolyte imbalance (decreased K+, Na+), hepatic encephalopathy
What medical disorders can cause depression? (5)
CV: CAD, CHF, MI
What medical disorders can cause depression? (6)
Neurological: AD, epilepsy, pain, PD, post-stroke
What medical disorders can cause depression? (7)
Malignancy
What psychiatric disorders can cause depression?
Alcoholism
Anxiety disorders
Eating disorders
Schizophrenia
Drug-induced depression
Lipid-soluble beta blockers
Psychotropics: CNS depressants (benzodiazepines, opioids, barbiturates), anticonvulsants, tetrabenazine
**Withdrawal from alcohol, stimulants
Corticosteroids, systemic
Isotretinoin
Interferon- ß-1a
DSM-5 for MDD (A)
At least 5 symptoms have been present during the same 2 week period and represent change from previous functioning
One of the symptoms must be depressed mood or loss of interest
What are the symptoms of MDD in DSM-5? (1)
In.SAD.CAGES
Interest: decreased interest and pleasure in normal activities
What are the symptoms of MDD in DSM-5? (2)
In.SAD.CAGES
Sleep: insomnia or hypersomnia
What are the symptoms of MDD in DSM-5? (3)
In.SAD.CAGES
Appetite: decreased appetite, weight loss
What are the symptoms of MDD in DSM-5? (4)
In.SAD.CAGES
Depressed: depressed mood
What are the symptoms of MDD in DSM-5? (5)
In.SAD.CAGES
Concentration: impaired concentration & decision making
What are the symptoms of MDD in DSM-5? (6)
In.SAD.CAGES
Activity: psychomotor retardation or agitation
What are the symptoms of MDD in DSM-5? (7)
In.SAD.CAGES
Guilt: feelings of guilt or worthlessness
What are the symptoms of MDD in DSM-5? (8)
In.SAD.CAGES
Energy: decreased energy or fatigue
What are the symptoms of MDD in DSM-5? (9)
In.SAD.CAGES
Suicidal thoughts or attempts
DSM-5 for MDD (B)
Symptoms cause significant distress or impairment in social, occupational, or other
important areas of functioning.
DSM-5 for MDD (C)
Symptoms are not caused by an underlying medical condition or substance.
Differential diagnosis (1)
Adjustment Disorder (with Anxiety and/or Depressed Mood)
Symptoms occur within 3 months of onset of a stressor; but once the stressor is terminated, symptoms do not persist for additional 6 months
Differential diagnosis (2)
Acute Stress Disorder
Symptoms occur within1 month of a traumatic event, and lasts 3 days – 1 month.
Symptoms include intense fear, helplessness, horror, with dissociation, re-experiencing, avoidance, increased arousal.
General assessment (1)
History of present illness
General assessment (2)
Psychiatric history
Any history of manic/ hypomanic episodes? (starting an antidepressant may cause “manic switch” in patients with underlying bipolar disorder)
General assessment (3)
Substance use history: Cigarettes/ETOH/substances
General assessment (4)
Complete medical & medication history
General assessment (5)
Family, social, forensics, developmental & occupational history
General assessment (6)
Physical & neurological exam
General assessment (7)
MSE for accurate diagnosis
- Assess suicidal/homicidal ideations and risks
- Reassess MSE on every interview to evaluate efficacy & tolerability
General assessment (8)
Labs
Vital signs, weight & BMI, FBC, U/E/Cr, LFTs, TFTs, ECG, FBG, lipid panel, urine toxicology
General assessment (9)
To exclude general medical conditions or substance-induced/withdrawal symptoms, e.g.
delirium/ psychosis/ depression/ mania/ anxiety/ insomnia/ thyroid disfunction/ diabetes
Gold standard rating scale
Hamilton Rating Scale for Depression
- By clinician
- Remission = HAM-D score ≤7 (therapy goal: symptom free)
Non-pharmacological
- Sleep hygiene
- Psychotherapy
- Neurostimulation (ECT, rTMS)
- Light therapy (for seasonal affective disorder)
1st line (antidepressant monotherapy)
Mirtazapine
SSRI
SNRI
Bupropion
Antidepressant indicated for ______ depression, not routinely indicated for _____ depression.
Moderate-severe
Mild
Antidepressants ± adjunctive meds selection is based on?
Target symptoms
Comorbidities
DDI
Prior response
Preference
Phases of treatment
i) acute phase
ii) continuation phase
What is considered adequate trial during acute phase treatment?
Adequate dose + duration (4-8 weeks)
What could cause delayed onset of effectiveness?
Gradual down-regulation of pre-synaptic auto receptors in synapse, which facilitates neurotransmitter release.
Time course of treatment response
Physical symptoms: 1-2 weeks to improve
Mood symptoms: 3-8 weeks (longer time)
Continuation phase duration
For 1st episode uncomplicated MDD: continue for at least another 4-9 months after acute phase treatment (total 6-12 months at least)
Examples of tricyclic antidepressants
Amitriptyline
Imipramine
Nortriptyline
Desipramine
Clomipramine
MOA of TCAs
Inhibits reuptake of serotonin and norepinephrine in presynaptic terminal, increasing concentration of these neurotransmitter in the synaptic cleft.
Which TCAs are non selective for 5-HT & NE neurotransmitters?
Imipramine, Amitriptyline, Nortriptyline
Which TCAs are selective for NE neurotransmitters?
Desipramine
Which is a 2nd generation TCA?
Secondary amines:
Nortriptyline
Desipramine
What receptors do TCAs have affinity to, causing AEs?
H1 histamine receptor antagonism
a1-adrenoceptor sympathetic block
Muscarinic receptor antagonism
AEs of TCAs
H1: sedation (can develop in 1-2 weeks)
a1: postural hypotension (dose related)
M1: dry mouth, blurred vision, constipation
Cautions in TCAs
Patients with history of MI: QTc prolongation, tdp
CV: cardiac conduction delays, heart block, arrhythmias
Which TCA can be used for OCD (other than depression)?
Clomipramine
Examples of SSRI
Fluoxetine
Fluvoxamine
Escitalopram
Citalopram
Paroxetine
Sertraline
Which is the least favourite SSRI?
Sertraline
Why do SSRIs have fewer AEs than TCAs?
Have a low affinity for other receptors including alpha1-adrenergic (α1), histaminic (H1), and muscarinic (M1) receptors
Fluoxetine approximately ___ folds selectivity for 5HT
50
Citalopram approximately ___ folds selectivity for 5HT
1000
What tolerability issues of TCA can affect its adherence?
Weight gain, sexual dysfunction
TCA is ______ on overdose.
Fatal
Most common dose-dependent tolerability issue of SSRI
Limited to 1-2 weeks after initiation or dose increase: GI symptoms
Somnolence, insomnia
Which SSRIs have long t1/2?
Fluoxetine: 4-6 days
Norfluoxetine: 4-16 days
Administration for Sertraline
Take with food to increase absorption
Which SSRI has more anticholinergic and antihistaminergic activity linked with increased sedation and weight gain?
Paroxetine
Citalopram
Which SSRI has short t1/2?
Paroxetine - withdrawal symptoms
Which SSRI can cause QTc prolongation if high dose in elderly?
Escitalopram/Citalopram
What tolerability issues of SSRIs can affect its adherence?
GI, sexual dysfunction
Examples of SNRIs
Venlafaxine (Desvenlafaxine - metabolite of Venlafaxine)
Duloxetine
MOA of SNRIs
Inhibits reuptake of serotonin and norepinephrine in presynaptic terminal, increasing concentration of these neurotransmitter in the synaptic cleft.
Venlafaxine and its primary active metabolite, desvenlafaxine, inhibit ____ reuptake at low doses, and ___ reuptake at higher doses.
5-HT, NE
Advantages of SNRIs
Claimed to work slightly faster than other anti-depressants and better in treatment-resistant patients
AEs of SNRIs
Same as SSRIs
Which SNRI increases BP?
Venlafaxine
Which SNRI causes urinary hesitation?
Duloxetine
What SNRI is indicated for diabetic peripheral neuropathy, fibromyalgia and chronic musculoskeletal pain?
Duloxetine
What to use for treatment resistant depression (TRD)?
Symbyax: Olanzapine 6mg + Fluoxetine 25mg
MOA of serotonin modulator and simulator (SMS)
Agonist activity at the 5-HT1A receptor
Partial agonist activity at the 5-HT1B receptor
Antagonism at the 5-HT1D, 5-HT7, and 5-HT3 receptors
Example of SMS
Vortioxetine
AEs of SSRI
GI & sexual dysfunction.
Headache, transient nervousness during initiation
Hyponatremia (SIADH)
Bleeding risk; EPSE
NaSSA
Norepinephrine and specific serotonin antidepressant
What drug class is Mirtazapine?
NaSSA
MOA of Mirtazapine
a. Enhances central noradrenergic and serotonergic activity through the antagonism of central presynaptic α2-adrenergic autoreceptors and heteroreceptors.
b. Antagonizes postsynaptic 5-HT2, 5-HT3, and H1 receptors resulting in anxiolytic, anti-nausea, and sedative effects, respectively.
Side effects of Mirtazapine
Somnolence
Increase appetite
Weight gain
Advantages of Mirtazapine
Reverse GI & sexual dysfunction
What drug class is Bupropion?
Norepinephrine-dopamine reuptake inhibitor (NDRI)
MOA of NDRI
No appreciable effect on the 5-HT reuptake
Inhibits both the NE and DA reuptake
When is NDRI useful?
Older adult patient - decreased motivation, low energy, fatigue
Side effects of NDRI
Seizure
Insomnia
Psychosis
When is NDRI unsuitable?
Eating disorder (imbalance of electrolytes can cause seizures)
Function of monoamine oxidase (MAO)
Breaks down monoamines (NE, 5-HT, DA)
Where are MAO found?
Nearly in all tissue
Intracellularly, mostly on mitochondrial surface
What is 5-HT broken down by?
Mainly MAO-A
What is NE broken down by?
Both MAO-A & B
What is DA broken down by?
Both MAO-A & B
Non-selective irreversible inhibitors of MAO-A & B
Isocarboxazid
Phenelzine
Tranylcypromine
AEs of Isocarboxazid, Phenelzine, Tranylcypromine
Hypertensive crisis
Why is tyramine restriction necessary?
Tyramine is usually metabolized by MAO-A in the gut and not absorbed into systemic circulation where it acts as a potent vasoconstrictor. Oral MAOIs block gut MAO-A resulting in absorption of tyramine.
Selegiline transdermal patch
Irreversible MAO-B inhibition
Which is the safest MAOi?
Moclobemide
Moclobemide
Reversible MAO-A inhibition
AEs of MAOi (1)
Postural hypotension
Due to sympathetic block produced by
accumulation of dopamine in the cervical (neck)
ganglia, where is acts as an inhibitory transmitter
AEs of MAOi (2)
Restlessness & insomnia
Due to CNS stimulation
MOA of tyramine
Taken up into adrenergic terminal, competes with norepinephrine for vesicular compartment, increase release of norepinephrine into synapses
Any antidepressant that increases serotonergic neurotransmission can be associated with _____.
Serotonin syndrome (especially increase release or duration of serotonin activity)
Serotonin syndrome symptoms
Mental status changes, autonomic instability, and neuromuscular abnormalities (eg, hyperreflexia, myoclonus)
MOA of Trazodone
Blocks reuptake of 5-HT;
Antagonizes 5-HT2A,H1 and a1 adrenoceptor
MOA of Trazodone
Blocks reuptake of presynaptic 5-HT;
Antagonizes postsynaptic 5-HT2A, H1 and a1 adrenoceptor
When is Trazodone more likely used for rather than depression?
Insomnia
SE of Trazodone
Priapism
MOA of Agomelatine
MT-1, MT-2 agonist
5-HT-2C antagonist
Increases DA and NE
What monitoring is required for Agomelatine?
LFTs
Contraindications of Agomelatine
Fluvoxamine
Ciprofloxacin
Both are strong inhibitors of the enzyme, increasing [agomelatine]
Adjunctive treatment for MDD
- SGA (Aripiprazole, Brexpiprazole, Quetiapine XR)
- Esketamine (NMDA receptor antagonist)
- PRN hypnotics
Esketamine dosing
1 session: 56mg or 84mg (lower in elderly)
Esketamine frequency
W1-4: 2 sessions/week
W5-8: 1 session/week
>W9: 1 session every 1-2 week, for at least 6 months
Benzodiazepines
Lorazepam
Potentiates GABA
Has dependence
Z-hypnotics
Zopiclone
Zolpidem CR
Preferentially binds to benzodiazepine-binding sites with Y and a1 subunits (causes sedation).
SEs of Z-hypnotics
Drowsiness
Taste disturbance (Zopiclone)
Complex sleep behaviors (sleep-walking)
Dependence
Maximum dose of Amitriptyline
300mg/day
Maximum dose of Clomipramine
300mg/day
Starting dose of Fluoxetine
20mg OM
Maximum dose of Fluoxetine
80mg/day
Usual dose of Mirtazapine
15-45mg/day
Therapeutic Lifestyle/Behavioral Changes
- Sleep Hygiene
- Exercise
- Relaxation techniques
Nutritional
- Vit. B12
– L-methylfolate
– Vit. D
– S-adenosylmethionine (SAMe)
– Omega-3 fatty acids
– 5-hydroxytryptophan (5-HTP)
Herbal
St John’s Wort
- Significant drug interactions with antidepressant
- Do not use concomitantly
Approaches to manage partial/no response (A)
Switch when completely ineffective or intolerable to adequate dose in 2-4w
(e.g. SSRI switched to SNRI, Mirtazapine, Bupropion, Agomelatine, or Vortioxetine)
Precautions during cross-titration
Watch for serotonin syndrome if combining serotonergic agents
Precautions when switching from serotoninergic antidepressant to non-serotoninergic antidepressant
Antidepressant Discontinuation Syndrome
- Gradual cross tapering over several weeks
What is needed when switch involves MAOi?
Wash-out period
Switch from Moclobemide to another antidepressant
24 hours wash out
Switch from another antidepressant to Moclobemide
Wash out at least 1 week
Wash out at leas 5 weeks if stopping Fluoxetine
Approaches to manage partial/no response (B)
Augmentation
How to augment?
Combine 2nd antidepressant with different MOA (must have partial response)
+ Mirtazapine, Bupropion-SR, T3 (Liothyronine), Lithium
Adjuctive SGAs: Quetiapine XR, Aripiprazole, Brexpiprazole
TRD (no response to ≥ 2 adequate trials of antidepressants)
- Neurostimulation: Electroconvulsive Therapy, repetitive Transcranial Magnetic Stimulation
- Symbyax® Oral Capsule (Olanzapine 6mg + Fluoxetine 25mg per Cap)
- Spravato® Nasal Spray (Esketamine 28mg per vial), as adjunct to SSRI/SNRI treatment.
Pregnancy
Consider Nortriptyline in late pregnancy (>28 weeks)
Breast feeding
Sertraline
Mirtazapine
PP depression
Brexanolone
Renal impairment
Vortioxetine
Hepatic impairment
Avoid Agomelatine
Mild-moderate: Vortioxetine
Post-MI depression
Sertraline
Elderly
Avoid TCAs
Hyponatremia
SIADH (usually in elderly)
ALL antidepressant, mostly SSRIs
Possibly lower risk with Agomelatine, Mirtazapine or Bupropion.
What to monitor for hyponatremia?
Serum Na at baseline, 2nd week, 4th week, then 3-monthly.
Common serotonergic agents (other than antidepressants)
Triptans
Sibutramine
Opioids (Tramadol, Fentanyl, Pethidine)
Dextromethorphan
Linezolid, Ritonavir (e.g. in Paxlovid®)
MAOI
SSRIs increases risk of _____________?
Bleeding.
Higher risks in elderly on NSAIDs, warfarin, steroids -> consider adding PPI
If patient has a scheduled surgery, which antidepressants require cautions?
Consider stopping serotonergic antidepressant 2 weeks before surgery if high bleeding risks
Which antidepressant is safest for patients with high bleeding risks?
Agomelatine
Drugs with fewer CYP interactions
Mirtazapine, Escitalopram, Venlafaxine, Desvenlafaxine, Vortioxetine
Which drugs has more apparent antidepressants discontinuation syndrome?
Paroxetine
Venlafaxine
What drug class is Paroxetine?
SSRI
What drug class is Venlafaxine?
SNRI
When does antidepressants discontinuation syndrome happens?
Abruptly stopping a regular treatment
Symptoms of ADS (Finish)
Flu-like symptoms (lethargy, fatigue, headache, achiness, sweating)
Symptoms of ADS (fInish)
Insomnia (with vivid dreams or nightmares)
Symptoms of ADS (fiNish)
Nausea (sometimes vomiting)
Symptoms of ADS (finIsh)
Imbalance (dizziness, vertigo, light-headedness)
Symptoms of ADS (finiSh)
Sensory disturbances (“burning,” “tingling,” “electric-like” sensations)
Symptoms of ADS (finisH)
Hyperarousal (anxiety, irritability, agitation, aggression, mania, jerkiness)
Onset of ADS
36-72 hours
Duration of ADS
3 - 7 days, typically resolve over 1-2 weeks without treatment
How to avoid ADS?
Gradually tapering
Which drugs do not require gradual tapering?
Fluoxetine
Bupropion
Due to long t1/2.
Patient counselling (1)
Antidepressants may take at least a couple of weeks to help with symptoms of low mood, poor sleep and appetite, may need at least a couple of months to help with anxiety
Patient counselling (2)
Do not take at same time as alcohol (space 4-6 hours part)
Patient counselling (3)
Tell your Drs & nurses what other medicines you are using
Patient counselling (4)
If your condition is worsening, or if you feel suicidal or bothered by side effects, contact Dr
(Suicide risk highest for children & adolescents ≤ 24 years old, hence need to monitor closely)
