Acronyms for Summarizing
Characteristics of Depression

SIGECAPS

SADIFACES

SIGECAPS

Sleep
Interests
Guilt
Energy
Concentration
Appetite
Psychomotor agitation or
slowing
Suicidal ideation

SADIFACES

Sleep – decrease or increase
Appetite – decrease or increase
Depressed mood
Interest (loss of)
Fatigue
Anxiety or agitation
Concentration (difficulty with)
Esteem (feelings of worthlessness)
Suicidal Thoughts or Ideations

What is depression?
Diagnostic specifiers for Depression

Depression with …
– Psychotic features
– With seasonal pattern (seasonal affective disorder – SAD)
– With melancholic features
– With atypical features (reversed physical symptoms)
– With peripartum onset
– With anxious distress

How often do episodes occur?

Episode frequency,
duration, and
intensity vary among
individuals and can
change intra-
individually over
time.

-more in teens and 20s

-moderate freq in 40s

-less in 50s and 60s

Causes of depression

-Multifactorial

A multifactorial, complex illness.
Optimal treatment ought to be
multifactorial also, addressing
biological, psychological, and
social factors.

Neurobiology of
Depression?

The underlying required pathophysiology required for
depression is unknown. There may not be a single specific
required neuropathological abnormality.

How alteration of functional
BDNF (BRAIN DERIVED NEUTROPHIC FACTOR)result in depression.

How alteration of functional
BDNF result in depression. In
brief, BDNF is a molecule
involved in the control of
synapse formation and
regulation of activity-
dependent changes in
synapse structure and
function. BDNF stimulation
increases synaptic spine
density by a mechanism
dependent on the Ras/ERK
pathway. Dysfunction or
decreased BDNF leads to
malfunction of synaptic
plasticity, and decreased
excitatory neurons and
glutamate; and eventually
lead to depression.

Dysfunction or
..... leads to
malfunction of synaptic
plasticity, and decreased
excitatory neurons and
glutamate; and eventually
lead to depression.

decreased BDNF

derease in synaptic plasticity =

decreased glutamate which leads to :

-decrease in synaptic transmission

-increase in neuronal degeneration

both leading to depression

decrease or dysfunctional BDNF (mutations- could lead to dysfunction of BDNF)

stress can be a factor

The Monoamine Hypothesis of Depression
• The Monoamine Hypothesis and Neurotrophic Factors
• Beyond Monoamines: The Neuroplasticity and
Neuroprogression Hypothesis of Depression

10-15 bullet points that help you develop an appreciation of and understanding of the complex neurobiology of depression
• Involves and goes beyond
monoamines
• Synaptic plasticity & BDNF
• Multiple factors lead to neurotrophic
dysregulation
• Stress and glucocorticoid release
impact sensitive brain region volume
and functioning
• Neuroinflammation and depression
• Circadian rhythm disruption and
depression

Anxiety Disorders (DSM-5)

Selected anxiety disorders:
• Panic Disorder
• Social Anxiety Disorder (Social Phobia )
• Generalized Anxiety Disorder

Other disorders (formerly classified as
anxiety disorders)

• Obsessive-Compulsive Disorder
• Post-Traumatic Stress Disorder

Treatments for Anxiety

• Psychotherapy
– First-line for mild-moderate presentations
• CBT (most common … multiple formats

Cognitive behavioural therapy (CBT)

“Third wave” CBT approaches:
Acceptance and commitment therapy (ACT)
Mindfulness-based cognitive therapy
Dialectical behaviour therapy
Psychodynamic therapy
Interpersonal therapy (IPT)

Drug therapy for anxiety

– For moderate-severe anxiety, combine with psychotherapy (ideal) or use alone:
• Antidepressants (acute & maintenance)
• Benzodiazepines (short-term/acute)

Rule of Thumb:Treatments for Anxiety

Drug therapy should be reserved for anxiety that interferes with daily functioning for which non-
drug interventions have failed or are not available, or at the outset when anxiety is severe.

ANTIDEPRESSANTS

First-line for depressive and anxiety disorders

ANTIDEPRESSANTS Mechanisms of Action

Enhance intrasynaptic catecholamine (5-HT, NA, DA) availability:

TCAs:

• amitriptyline
• amoxapine
• desipramine (Norpramin)
• doxepin
• imipramine (Tofranil)
• maprotiline
• nortriptyline (Pamelor)
• protriptyline (Vivactil)
• trimipramine (Surmontil)

serotonin and noradrenaline reuptake inhibition

They are a good choice for those whose depression is resistant to other drugs, but some may find their side effects unpleasant

§ SSRIs: selective serotonin reuptake inhibitor … aka SERT antagonist

-§ SSRI+: serotonin reuptake inhibition PLUS other putative (widely accepted) antidepressant pharmacological actions

-cause GI sx-bcus we have 5ht receptors in gut

-sexual dysfunction

-sx go away in a couple of days

SNRIs: serotonin and noradrenaline reuptake inhibition … aka SERT + NET antagonist.

-SERT + NET antagonist=serotonin and norepinephrine transporter antagonists

actions of this drugs include :

-irritation, agitation, hair at the back of neck erection, alert, tremors, jump out your skin.

-do not take HS

§ NDRIs: noradrenaline and dopamine reuptake inhibition … aka NET + DAT antagonist

DAT=dopamine transporter

NET=norepinephrine transporter

NaSSA: alpha-2 receptor antagonist →

NA and 5-HT release + serotonin antagonist

MAOIs:

inhibit metabolism (deamination) of catecholamines

Dry mouth. Nausea, diarrhea or constipation. Headache. Drowsiness. Insomnia. Dizziness or lightheadedness. Skin reaction at the patch site.

Catecholamines

dopamine and adrenaline, are hormones that the brain, nerve tissues, and adrenal glands produce. They are responsible for the body’s “fight-or-flight” response.

Dopamine, adrenaline, and noradrenaline are all catecholamines. The body releases catecholamines in response to emotional or physical stress.

REMEMBER:
DEPRESSION IS NOT A DEFICIT OF ...

CATECHOLAMINES

Neurotransmitter balance
5HT vs. NA (noradrenergic)

balance

Desipramine
Nortriptyline
Doxepin

Increasingly Noradrenergic =

Focused
Alert/vigilant
Hyperarousal
Tense

milnacipran
Duloxetine
Amitriptyline
Imipramine
Venlafaxine
Clomipramine
Fluoxetine
Paroxetine
Sertraline
Citalopram
Escitalopram

Increasingly Serotonergic
Reduced emotional response
Apathy
Nausea
Sexual dysfunction

Clomipramine

most serotonergic effect

Antidepressants: More Than Catecholamines

§ The hippocampus & PFC exhibits stress-sensitive structural plasticity
§ Stress reduces hippocampal and prefrontal cortex neuronal volume
§ Animal studies have shown that stress decreases neurogenesis
§ Antidepressants reverse the effects of stress; neuroprotective action
§ It is not clear that low hippocampal/prefrontal volume is associated with depression,
but BDNF-produced neuronal volume regeneration (growth) seems to be a
requirement for an antidepressant response
§ The role BDNF in antidepressant response has been observed with standard
antidepressants (gradual onset) and ketamine (fast onset)

Animal and human studies indicate that brain-derived neurotrophic factor (BDNF) is.....

involved in the pathogenesis of depression and antidepressant response

....... reverse the effects of stress; neuroprotective action

§ Antidepressants

It is not clear that low hippocampal/prefrontal volume is associated with depression,
but ........ regeneration (growth) seems to be a
requirement for an antidepressant response

BDNF-produced neuronal volume

The role BDNF in antidepressant response has been observed with .......

standard antidepressants (gradual onset) and ketamine (fast onset)

fluoxetine has a ...............

mirtazapine has an alcohol drug to drug interaction which is

long t1/2

a PD interaction

Antidepressant Potency at Other Receptors.

Antagonist action

Antidepressant Potency at Other Receptors at Muscarinic-common adverse effects

TCAs WITH ki value <1 to 100 (high and moderate to high) will cause more:

delirium

memory impairment

blurred vision

dry mouth

reduced GI motility

which TCAs have ki 100-200 (moderate antagonism)

desipramine,
nortriptyline,
paroxetine

antidepressants will cause moderate side effects at muscarinic receptors of individuals taking these.

which TCAs have ki> 200(high ki=low potency)

bupropion, SSRIs,
SNRIs

-would cause low adverse effects (Delirium, memory
impairment, blurred
vision, dry mouth,
reduced GI motility)

Antidepressant Potency at Other Receptors

Histamine H1

high and moderate to (hi ki<1-100=mirtazapine) would cause sedation and weight gain

desipramine is a would cause moderate adverse effects because .....

its ki value is 100-200

bupropion, SSRIs,
SNRIs

these tcas would cause low side effects because because their ki value is high >200

Antidepressant Potency at Other Receptors

TCAs with hi and mod to high ki value(<1-100) e.g trazodone

Dizziness

orthostatic hypotension

reflex tachycardia

at

moderate Dizziness, orthostatic
hypotension, reflex
tachycardia

at

low Dizziness, orthostatic
hypotension, reflex
tachycardia.

because of their high ki values >200

Antidepressant Selection (1st line): Relative Intolerability

based on GI N/V

VFX (SNRIs) > Fluoxetine > other SSRIs

these s/e diminish over time

Antidepressant Selection (1st line): Relative Intolerability

based on diarrhea

Sertraline > others

Antidepressant Selection (1st line): Relative Intolerability

based sexual dys

Paroxetine > SSRIs (25-50%) (citalopram25%) > SNRIs 25% >> BPR, MTZ, MLB[<10%]

ranked from high probability of causing sexual dys.

Paroxetine > SSRIs (25-50%) (citalopram25%) > SNRIs 25% >> BPR, MTZ, MLB[<10%]

Sweating Paroxetine > others

no diminution over time

Sedation

Mirtazapine > Paroxetine > others

possible diminution overtime

Weight gain

Mirtazapine > Paroxetine > others

maybe possible diminution overtime

BP-incrz

NRIs (VFX, DLX, BPR)

-NRIs not good for people with high BP

no diminution over time

Withdrawal”

Paroxetine, venlafaxine > SSRIs >> fluoxetine

-taper always

Hyponatremia

SIADH of concern with all ADs

Seizures

BPR > others

Switching & Combining Antidepressants

Common, safer combinations:
Mirtazapine + SSRI/SNRI
SSRI/SNRI + trazodone
Mirtazapine + bupropion
SSRI/SNRI + bupropion

Combinations with +++++ risk

MAOI + other AD (antidepressants) (avoid)
RIMA + other AD (avoid)
TCA low dose +
SSRI/SNRI/bupropion/trazodone
/mirtazapine (check PK interactions)

MAOIs: monoamine oxidase inhibitors
Moclobemide, phenelzine, tranylcypromine

Nomenclature:
• MAOI: phenelzine, tranylcypromine
– Non-selective (A&B), irreversible
• MAO-A inhibitor: moclobemide (RIMA)
– Selective, reversible, competitive inhibitor
• MAO-B inhibitor: selegiline, Rasagiline
– Selective, irreversible

Can antidepressants be overlapped or combined?

A: Yes. This is commonplace.
Usually safe, with dangerous, possibly deadly exceptions

when switching AD

Anti-depressant---(5t1/2) b4 starting MAOI (tranylcypromine(Parnate)
Phenelzine (Nardil)---(wait 2 weeks b4 switching to another Anti-depressant)

-also wait 5t1/2 b4 switching to-RIMA(Moclobemide (Manerix)) follow with another 5 t1/2 if switching to another.

Fatal interactions with MAOI

Serotonin syndrome

Garbage system malfunctioning
MAOIs substantially reduce the
metabolism (clearance) of neuronal
serotonin.
Supply system hyperactive
Drugs (and substances) that enhance
neuronal concentration of serotonin
(e.g., SRI

Hypertensive crisis

food- drug interaction

Garbage system malfunctioning
MAOIs substantially reduce the
metabolism (clearance) of neuronal
noradrenaline.
Supply system hyperactive
Substances (and drugs) that enhance
neuronal concentration of
noradrenaline (e.g., tyramine in
cheese)

Serotonin Syndrome (severe)

confusion

fever-tylenol wont work

shaky

autonomic instability -hypertensive

tachycardia

mydriasis

agitation

tremor

diaphoresis

increased bowel sounds

hyperflexia-greater in lower extremities

Clinical Presentation serotonin synd

signs and symptoms can be classified into into three
groups:

Autonomic dysfunction: fever, tachycardia, diarrhea, hyperactive
bowel sounds, diaphoresis, pupil dilation
– Neuromuscular: hyperreflexia (especially in lower extremities),
shivering, clonus (inducible, spontaneous, ocular), myoclonus,
tremors, muscular rigidity
– Cognitive: anxiety, agitation, restlessness, hypervigilance, pressured
speech, agitated delirium

Autonomic dysfunction: signs and sx of serotonin synd

fever,

tachycardia,

diarrhea,

hyperactive bowel sounds,

diaphoresis,

pupil dilation

Neuromuscular

signs and sx of serotonin synd

hyperreflexia (especially in lower extremities),
shivering,

clonus (inducible, spontaneous, ocular),

myoclonus,
tremors,

muscular rigidity

Cognitive:

signs and sx of serotonin synd

anxiety,

agitation,

restlessness,

hypervigilance,

pressured speech,

agitated delirium

Serotonin Syndrome (severe)

life threatening toxicity

met acidosis
rhabdomyolysis
seizures
renal failure
DIC

what are mild sx of serotonin synd?

akathisia

what are some serious sx of serotonin synd?

hyperthermia

hypertension

muscular hypertonicity

moderate sx of serotonin synd?

tremors

altered mental state

clonus induced

Always recognize the names of the MAOIs:

-Phenelzine (Nardil®)
-Tranylcypromine (Parnate®)
-Isocarboxazid (Marplan U.S.A only)
-Moclobemide (Manerix®) – less risky due to MOA

Monoamine Oxidase Inhibitors (classic type)

-Phenelzine (Nardil),

-tranylcypromine (Parnate)

Effective for depression, especially treatment refractory depression and atypicaldepressive episodes

Monoamine Oxidase Inhibitors (classic type) Common side effects include

Dizziness and lightheadedness
– Weight gain and fluid retention
– Sexual dysfunction
– Insomnia

**MAOI Precautions:

– drug and food interactions!!!!!!

Substances (and drugs) that enhance
neuronal concentration of
noradrenaline (e.g., tyramine in
cheese)

MAOIs: Food and Drug Restrictions

Food (apply to tranylcypromine and
phenelzine only)
Absolute
• aged cheeses
• cured meats
• tap beer
• sauerkraut
• Marmite/Vegemite
• fava & broad beans
• Conc. soy products
Moderation
• bottled beer and wine (2 glasses)

which drugs interact with MAOIs Drug (apply to tranylcypromine, phenelzine, and moclobemide)

Drug (apply to tranylcypromine, phenelzine, and
moclobemide)
Prescription
• SSRIs/TCAs/Venlafaxine
• meperidine (Demerol)
• L-tryptophan
• L-dopa
• epinephrine/norepinephrine
• stimulants: methylphenidate, amphetamine,
phentermine
• hypoglycemic agents
Non-prescription
• decongestants (pseudoephedrine, etc)
• dextromethorphan (DM)
Street: cocaine

Antidepressant Selection

–Patient preference
–Past response
–Subtype of depression
–Symptoms
–Suicide risk
–Toxicity in overdose
–Medical history
–Drug interactions
–Adverse effect profile
–Fertility status
–Convenience
–Cost

Antidepressants: How Do They Compare?

What is mostly the same?•

Overall benefits
• Time to see benefits
• Chance of benefiting
- Somewhat: 80%
- Significantly: 60-70%
- Completely: 50%

Chance of stopping Rx prematurely
->50% within 3 months
• Duration of treatment
-1st or 2nd episode: 6-12 months
->2 episodes close together: >1
year to indefinitely

Antidepressants: How Do They Compare?What is different?

Individual response
• Side effects
• Drug interactions
• Precautions
• Cost
• Dosing
• Chance for side effects when
stopping treatment
• Drug-drug, drug-disease, drug-food
interactions
• Specific pharmacological actions
• Patient preferences

Achieving remission often requires....

multiple
antidepressant
trials

Treatment Goals

Short-term (8-12 weeks):
Reduction in symptoms to full remission
An improvement in quality of life
Return of normal level of functioning
Long-term (>3 months):
Prevention of a return of depressive or anxious symptoms
Maintenance of a stable mood
End of treatment:
Reduce or eliminate risk for discontinuation symptoms

Antidepressants: Onset of Effect

Weeks 2-4:

improved
sleep, appetite,
energy

Weeks 4-8:

depressed mood, loss of
pleasure, pessimism, irritability
significantly improve

Months:

slow return
of functioning

Stages of Treatment with Antidepressants

response/remission

6-12 weeks

recovery/relapse

4-9 months

recurrence

1 or mo yrs

Relapse prevention with antidepressants is impressive

NNT: 3-6
For every 3-6 people in which
treatment is extended for 1-2
years, an additional person
avoids relapsing.

SSRI/SNRI Discontinuation Syndrome
Can be VERY DISTRESSING, DISABLING

Common with abrupt cessation of SSRI or SNRI

1-2 weeks of feeling “off” or “flu’ish”, occ. protracted course

Common: dizziness, anxiety, nausea, sweating, coryza, headache, insomnia
Occasionally: shock-like sensations, parasthesias, visual disturbances, myalgias, chills, confusion

SSRI/SNRI Discontinuation Syndrome

Management:

Prevent by advising patient not to stop SSRI/SNRI cold turkey (exception fluoxetine)
Taper SSRI/SNRI over 1-4 weeks
If mild symptoms: encourage them to try to let it pass over 1-2 weeks
If moderate to severe or symptom > 2 weeks REINTRODUCE SSRI and taper more slowly or switch to fluoxetine (long t1/2) then taper

TREATING DEPRESSION IN YOUTH

ANTIDEPRESSANT EFFECTIVENESS AND SAFETY

Overall relative risks (RR) of suicidal behavior or ideation by drug
(26 pediatric trials- 16 MDD)

venlafaxine RR =8.84(1.12, 69.51)

paroxetine =2.15 (0.71, 6.52)

In Pediatrics
Overall relative and absolute risk of suicidal behavior or ideation

For every 100 pediatric patients treated, 2 to 3 patients have
some increase in suicidality during short-term treatment, (i.e.,
beyond the risk with the disease being treated)

Treatment for Adolescents With Depression Study (TADS)

Design:
– MC, RCT, 12 weeks
Patients:
– moderate to severe depression
– included comorbid illnesses
– N=439, 12-17 years
Interventions:
– Fluoxetine 10-40 mg/day
– CBT + fluoxetine
– CBT alone
– Placebo
Outcomes
– Children’s depression scale, Clinical Global Impression for
Improvement (CGI-I)
– Suicidal Ideation Questionnaire (29% suicidal at baseline)
– Prospectively assessed ‘suicide-related’ and ‘harm-related’ events

TADS CGI Responders
• Placebo 35%
• CBT alone 43%
• FLU alone 61%
• Combo CBT/FLU 71%

Combo FLU + CBT was superior to PLA (p = .001),

FLU alone(p= .02), and CBT alone (p = .01)
FLU alone was superior to CBT alone (p = .01

TADS
Adolescents with Depression
Demonstrated:

• Fluoxetine to be more effective than placebo and CBT alone
• Reduced suicidality across treatments (including placebo) but level of reduction varied (smallest mean reduction with fluoxetine alone)
• Fluoxetine associated with more self-harm vs. CBT or placebo

Information about suicide

• 20-100 attempts for every successful suicide
• Women: more attempts than men
• Men: more suicides than women
• Most common methods:
– Attempts: overdose
– Death from suicide: hanging (men); overdose (women)

Previous non-suicidal self-harm
Previous suicide attempt
Psychiatric illness
Psychiatric hospitalization
Mood disorder
Personality disorder
Female
Less than 30 years
Relationship difficulties

Risk factors for suicide attempts

The leading method of suicide attempt involves medication overdose

-poisoning 86.1%

1 in 6 repeat overdose

After deliberate overdose (ED visit or hospitalization

With a median 5.3 year follow-up:
6.3% die (all cause)
1.5% die from suicide(42-fold higher risk of suicide Median time to
suicide: 1.6 years)
0.6% die from intentional overdose
highest risk: seniors

An intentional overdose represents a powerful
marker for future suicide attempt and suicide risk.
What can pharmacists do?

Inquire,
acknowledge & communicate Plan & follow- up Document Limit access to
means Find other supports

CLINICAL PEARLS

Antidepressants & alcohol:

Can I drink alcohol with this medication?”
– Is the antidepressant sedating?
– How much alcohol and what will be its effect on mood stability?

Most commonly used antidepressants are not “ sedatives” and do not substantially add to the impairing effects of alcohol … when consumed responsibly
– SSRIs, venlafaxine, bupropion, desipramine
Most people with mood disorders (e.g., depression) are vulnerable to alcohol’s effect on mood stability. All patients taking antidepressants should be encouraged to limit their alcohol intake to a minimum to allow for improvement and stabilization of mood

The more severe the depressive episode,the more the scale tips in favour of using an ....

antidepressant.

Antidepressants are more effective for
..............
Beware of bipolar depression

anxiety disorders than for depression.

At first try, the chance for achieving
remission of depression is....

< 50%

For depression, antidepressants are better at keeping people well vs. .....
(NNT Keep well < NNT Get well )

getting them well.

Selecting an antidepressant

....is much more about the process and less about the decision.

Early...... is substantial and can be mitigated.

non-adherence

• Not like the others:
– Non-serotonergic
– Reduces depression-related anxiety; not an anxiolytic
– Mixed spectrum: ADHD, smoking cessation
– No withdrawal reactions
– Absence of sexual side effects
– Side effects/precautions:
• Seizure disorder – avoid
• CNS stimulant-like side effects (warn patients

NDRI: Bupropion

Advice: Have you ever had a seizure or epilepsy?
This medication can make you feel quite restless in the beginning …

TCAs: Tricyclic antidepressants

Amitriptyline,

clomipramine,

desipramine,

doxepin,

imipramine,

nortriptyline,
trimipramine

Amitriptyline:

– Remains in common use
– Sedative, neuropathic pain, depression,
anxiety

Clomipramine:

– SSRI-like mechanism
– Obsessive-compulsive disorder

Desipramine:

– Noradrenergic
– Reasonably tolerated
– Not sedating

Nortriptyline:

– TCA of choice for depression
– Blood levels useful

TCAs: Tricyclic antidepressants

• Multiple pharmacological effects –
desired and undesired
• Serotonin and noradrenaline
reuptake blockers
• Block histaminic, alpha adrenergic,
and muscarinic receptors causing …
– Sedation, appetite stimulation
– Dizziness (upon standing) – risk for falls
– Anticholinergic side effects (dry mouth …confusion)
• Cardiovascular toxicity
• Dangerous in overdose
• Safe and effective when used in
appropriate patients

- Vortioxetine
- SRI
- Additional direct effect on serotonin
receptors with multiple theoretical clinical
implications
- No advantage observed for depressive symptoms vs. other antidepressants
- Numerical advantage on the digit symbol substitution test (DSST, an assessment of cognitive processing speed, attention, working memory) of uncertain clinical importance

SSRI+

aka trintlex used to treat major depressive disorder

Vortioxetine works by increasing the activity of a chemical called serotonin in the brain.

Ketamine and its enantiomers r,s

Indicated in combination with a SSRI or SNRI, for the treatment of major depressive disorder in adults who have not responded adequately to at least two separate courses of treatment with different antidepressants, each of adequate dose and duration, in the current moderate to severe depressive episode.

Ketamine and its enantiomers r,s Formulations

1. Ketamine infusion
2. Esketamine nasal spray (Health Canada approved)

1. Ketamine infusion: none for mental illness
2. Esketamine: treatment-refractory depression when combined with SSRI or SNRI (Spravato®, Health Canada)

Practicalities

Ketamine and its enantiomers r,s

2. Specialized infusion/administration clinic
Post-admin observation: ≥ 2 hr
Post-admin precaution: no driving, etc. till next day

Dosing

Ketamine and its enantiomers r,s

2. Induction phase (4 weeks): twice weekly
2. Maintenance phase (5-? weeks): q1w x 4, q1w or q2w x ? weeks

Ketamine and its enantiomers r,s

action

NMDA receptor antagonist