Module 3- Disease Treated by psychiatrists:
3.1.1 (1st vs 2nd generation Antipsychotic Agents):
What are antipsychotics drugs?
- They are the drugs of choice for the management of schizophrenia.
st
(1 gen) Conventional Antipsychotics (FGA)
1st generation antipsychotics = also called conventional antipsychotics.
How are each of these medications different from each other?
- This depends on the variability in terms of effects, so there are often categorized in
terms of potency which has to do with extrapyramidal effect.
Potency:
- Low potency group like chlorpromazine has moderate- low Extrapyramidal effect.
- High potency group like Haloperidol have high to very high Extrapyramidal effect.
The extrapyramidal effects:
- These are linked to affinity for dopamine receptors. High extrapyramidal effect = High
affinity to bind to dopamine receptors.
High potency vs Low potency related to dopamine: positives vs negatives
- High potency= Higher affinity to bind with dopamine receptor results in lower affinity to
bind to other receptors such as sedation, orthostatic hypotension, anticholinergic
effects etc.… ( lowers the other forms of toxicity)
- while for Low potency you have a lower affinity to bind to dopamine receptors meaning
you have higher forms of the other toxicity.
Qt prolongation -> related to cardiac effect ( so keep in mind when choosing a medication)
(2nd Gen) Atypical Antipsychotics (SGA)
2nd generation = also called atypical antipsychotics
What was the objective of the 2nd gen compared to 1st gen?
- it was to keep the efficacy of the first generation and just make them have low
extrapyramidal effects.
2nd gen has low extrapyramidal effect, what happens to the other toxic effects such as
sedation orthostatic hypotension and anticholinergic effect?
- It's very variable, some have low effects and some have high or moderate. So there's a
lot more variability here.
What toxicity is much higher/ different with 2nd generation compared to the 1st generation?
- Metabolic effects such as weight gain, diabetes, risk of dyslipidemia
Comparison of 2nd gen to 1st gen:
- Believed to have superior efficacy
- They have lower extrapyramidal effect which led to much more variability with other
toxicity and now has metabolic effects compared to 1st gen. so overall they are different
but no better toxicity profile.
- 10-20 x more expensive than 1st gen because they are newer.
Mechanism of action and use:
The mechanism of action of antipsychotics:
- A lot of it is still unknown or aren't clear.
Therapeutic effect hypothesis:
- Most of the drug stole their benefits via D2 (dopamine, D2, subtype antagonism in the
brain).
- This effect would help mostly in the improvement of positive symptoms and not other
symptoms.
- RECAP: The positive symptoms is due to the increased dopamine activity in certain parts
of the brain and the negative symptoms would be reduced dopamine activity in other
parts.
- hypothesis about potentially serotonin antagonism 5-HT
 Some second-generation drugs like clozapine have more affinity for the
serotonin 5-HT 2A receptor, more so than the D2 dopamine receptor.
Hypothesis for adverse effects like sedation or orthostatic hypotension
- is due to the blockage of histamine, norepinephrine, and ach receptors.
When do we use these drugs?
- These drugs are used for acute psychosis, abortion, and prevention, so they are efficient
for that.
- The onset of effects takes 1-2 days, but it is an example of a drug that has a delayed
onset effect as well, and that it increases over time so that the peak effects and the
peak benefits is usually achieved within 2-4 weeks.
- Variable efficacy for 3 types of Sx depending on the drug used. So some drugs help
with negative sx while others help with cognitive sx.. leads to trial an error with the
drugs prescribed for the individual.
- All the drug have somewhat of a similar efficacy profile to one another.
- The agents should be much more selective based on the toxicity profile so that we
maximize adherence.
This meta-analysis found that with few exceptions, only clozapine, amisulpride, zotepine,
olanzapine and risperidone were significantly more efficacious for the primary outcome, which
was symptom relief. As you might notice that most of those are second generation
antipsychotics, so it seems like it is true that the second Gen did have some improvement in
terms of efficacy.
Most effective Antipsychotics:
Most effective antipsychotics: Clozapine, Risperidone, Olanzapine.
Which drug is the best #1 in terms of Extrapyramidal effect: Clozapine.
- Why? Has least extrapyramidal effect. That's because it has weak dopamine inhibition,
which would support the hypothesis that they're due to dopamine blockage.
- Negatives?
 Clozapine has high sedation and anticholinergic effects.
 High metabolic effects like olanzapine.
 Clozapine also has QT prolongation but olanzapine does not, so if an individual
has heart problems then you would favor olanzapine.
In terms of prolactin elevation:
- only risperidone had this effect between those three.
In terms of metabolized by CYP3A4:
- Clozapine the only one out of the 3
- Recap: CYP3A4 = more drug interactions
Clozapine:
Indications:
Most effective antipsychotics
Excellent for patients with severe EPS
Try safer alternatives 1st due to Safety Alert
-
Clozapine most effective and number 1.
Positive about clozapine: Has low extrapyramidal symptoms which is great because
that's one of the common reasons why patients would discontinue treatment or stop
taking their meds = inc adherence.
Safety Alert: Fatal Agranulocytosis
Unknown mechanism / 1-2% of patients
Onset in first 6 months / Monitor WBC weekly
Patient Education on risks & early Sx
-
Negatives about clozapine: it also has a lot of other toxicity, and there's a final one is
Fatal agranulocytosis.
- Fatal agranulocytosis:
 That were observed with individuals on clozapine.
 The mechanism is unknown, but we know that it affects about 1 to 2% of
patients, which is significant.
 The onset of it would appear in the first 6 month. So, because of that, the white
blood cell count must be monitored weekly so that the drug should be
discontinued if excessive effects on that number are observed
 Patient education on risk and early symptoms is crucial.
Is clozapine the first drug of choice? NO
 Due to the fatal risk, Clozapine is never recommended as a 1st line antipsychotic.
 It's always recommended that we try a safer drug first, even if it's not as
effective because if the safer drug works, then we don’t need clozapine.
 Therefore, a safer alternative has to be used first and clozapine is only kept for
patients with let's say a lot of EPS (extrapyramidal symptoms) or who are not
responding to other treatments.
3.1.2 Antipsychotics toxicity:
Extrapyramidal symptoms (EPS):
Extrapyramidal symptoms: most common with 1st gen drugs.
- one of the major toxic effects of antipsychotic drugs.
- They refer to the fact that they influence the extrapyramidal pathways of motor control.
- pathway that controls motivation oriented movements in the sense that voluntary
movements, goal oriented decisions, like for example reaching your arm to go grab a
glass of water.
- Extrapyramidal symptoms refer often to lack of control of those movements.
Early reactions:
- Such as a muscle spasm in the face and neck.
- Symptoms resembling a lot Parkinson, so slow movement mass like face, facial
expression, tremor, rigidity, etc.
- Sometimes it could be quite the opposite. It could be compulsive, restless movements,
symptoms of anxiety or agitation so very strong tremors.
Late reactions: so meaning in in terms of like months to years to develop but that can happen
with individuals who have been on antipsychotics for a long time.
- Tardive dyskinesia -> choreoathetoid movements which are more similar now to what
you would see in Huntington's disease. (MORE SEVERES REGARDING EPS)
Management of the reactions:
- Anticholinergics drugs or benzodiazepine if EPS is observed.
Antipsychotics toxicities: ½
Adverse Effects
Notes
Neuroleptic Malignant Syndrome (NMS)
Potentially fatal syndrome more likely with High-Potency
FGAs (ex.: Haloperidol)
Sx: Rigidity / Sudden fever / Autonomic dysfunctions /
Consciousness alterations
Management: Dantrolene (muscle-relaxant) &
Bromocriptine (DA Agonist)
Anticholinergic Effects
Manifestations: Dry-mouth / Constipation / Urinary
Retention
Orthostatic Hypotension
Via blockade or α1-adrenergic receptors → No
compensatory vasoconstriction
Monitor BP & Pulse rate
Sedation
Via blockade of Histamine H1 receptors → ↓↓ over time
↑ Prolactin levels
Via DA inhibition → DA cannot inhibit prolactin release
Manifestations: Menstrual irregularities / Breast growth /
Galactorrhea
↑ Seizure risk (unlikely to cause seziure… only
happens if the pt already has a diagnostic of seizure
disorders exacerbates it. )
Problematic in patients with seizure disorders
Adjust anti-seizure medication dosage up if necessary
Sexual Dysfunction (common theme for many CNS
drug like antipsychotics, antidepressants etc.) main
reason for decline in pt adherence.
↓ Libido + Erectile dysfunction → ↓ Patient adherence
Low-Potency FGAs > High-Potency FGAs
 Some side effects like orthostatic hypotension or sedation is due to binding of the
Cholinergic, adrenergic and histamine receptors.
Antipsychotics toxicities: 2/2
Adverse Effects
Notes
Agranulocytosis
Very rare → Monitor WBC count if sign of infection
Most likely with Chlorpromazine & Clozapine
Severe Dysrythmias
(QT Prolongation)
Chlorpromazine & Haloperidol prolong QT interval
ECG & potassium determination before & after Tx
Effects on Dementia patients
Off-label use → Doubles mortality risk → Avoid at all
cost!!
Teratogen
Risk of EPS to baby if exposed during 3rd trimester
Not recomended to discontinue Tx → Monitor
instead
Physical Dependence
Addiction and abuse are unlikely (LOW RISK)
Mild withdrawal Sx if abruptly stopped → Taper off
gradually ( They should be tapered off gradually to
allow the CNS to adapt)
Drug Interactions
(MAJOR ONE) Anticholinergic drugs → ↑
Anticholinergic effects
( OTHER ONES) Alcohol & CNS depressants →
Additive effects
L-DOPA → Antagonistic effects and vice versa ( L-dopa
inc dopamine in the brain results in the opposite
effect)
Teratogen -> so if a patient was on antipsychotics and then they become pregnant etc. It's not
recommended to discontinue the drug because even though they are teratogen. The risk to
discontinuing the drug impacts the future mother more than the potential risk to the fetus, so
it's best to monitor instead and then only act if there is clear indication that there is teratogenic
effect, not just a hypothetical risk.
3.1.3- Schizophrenia Management:
Schizophrenia management: ½
3 Major Objectives:
1) Acute episode suppression
2) Prevention further acute psychosis
3) Improve Quality of Life (Daily functioning)
Drug Selection
1) It should be Individualised based on efficacy/toxicity/cost
Example :
- if they have History of diabetes? → Avoid Rx with Metabolic effects
- if they are Resistant to initial Tx? → then favor most efficient ssecondary
drug like Clozapine, Olanzapine, etc.
- if the patient has No contraindications? → then use Cheaper Rx
Administration Strategies
1) Bedtime dosing ↓(dec) daytime drowsiness/sedation
2) Higher dosage for acute psychosis vs. Lowest effective dose for maintenance
3) Acute therapy: PO preferred → Liquid formulations must be diluted before
admin
4) If Prevention: IM Depot preparations → ↑ adherence + ↓ toxicity ( because
then it's like a larger dose that is deposited in the muscle tissue and it will just
diffuse at a gradual rate within the system so it increases adherence because
the patient can't really forget to take their dose because it's already in there and
it reduces toxicity because the concentration will be in a steady state for much
longer)
Schizophrenia management:2/2
Acute Therapy
- Sx ↓ 1-2 days
- 1-2 weeks for significant
improvement
- Full effect over few months
Maintenance Therapy (prevent future psychosis)
- Treat for at least 12 months after post-acute episode → problem is that it
leads to Poor adherence since 12 mo is a long time.
- If pt is Sx-free after the 12 mo : Taper off gradually to ↓ withdrawal symptoms
 Favor IM Depot (long-acting) preparations to improve adherance and
reduce toxicity.
Other ways to Promoting Adherence & Nondrug Therapy :
1. Cognitive Behavioral Therapy: Forming therapeutic alliance & support system with the family,
psychotherapist or social network of the pt.
2. Patient & Family education : Strict schedule & adherence; educate individuals that there is a Low
risk of addiction
3. Vocational training : very beneficial to individuals with schizophrenia. It Provide feelings of agency,
productivity & independence. This can help with the improvement of the third objective which was
improve QoL and daily functioning, which can help the pharmacoligical aspect by boosting the
placebo effect.
Adjunct Drugs : co- administered with antipsychotics
1) Benzodiazepines: management of EPS + ↓ anxiety + stabilize sleep
2) Antidepressants for depressive Sx ( comorbidities between psychosis
and depressive symptoms)
3.2.1 bipolar therapy : drugs for bipolar disorder
Bipolar disorder (BPD) therapy:
1) Include Nondrug Therapy: See Antidepressant Section for more Details
2) Healthy Lifestyle & Psychotherapy:
 Always adjunct to Rx therapy (psychotherapy should always be combined with
the pharmacology aspect)
 Develop coping skills & Resiliency (drug should favor both)
3) Electroconvulsive Therapy (ECT):
 Reserved for patients unresponsive to Rx (drugs) + Psychotherapy
Major drug class for Bipolar disorder therapy:
Major Rx Class
for BPD Therapy
Class
Mood stabilisers
Antipsychotics
Antidepressants
Preferred Drugs
Lithium
Valproate
Carbamazepine
SGA > FGA
Second gen> first gen
SSRIs
Buproprion
Notes
1st-line options:
- They Abort Manic
Episodes
- Prevent
Recurrence of
future episodes
Adjunct to Mood
Stabilisers for Severe
Manic Episodes
Adjunct to Mood Stabilisers
for Severe Depressive
Episodes
Drug selection: depends on the situation
Drug Selection
Situation
Acute Manic Episodes
1) Lithium or Valproate
 Add SGA if Severe
2) Benzodiazepine
included if theres
Insomnia & Agitation
Preferred Drugs
Notes
2+ weeks for Optimal
Response (DELAYED ONSET
EFFICACY)
Acute Depressive Episodes
Long-Term
Prevention
Mood Stabilisers
Mild: Mood Stabilisers alone
If un responsive after a while
you can add +Antidepressant
if unresponsive.
You can Add SGA if
frequent relapse
especially for mani
episodes
 There's a bit more emphasis on the manic episodes because they're considered to be a
bit more unpredictable in terms of what the patient can do for their own health and
that of others.
 Whereas for depressive episodes, even though they're unpleasant, there's less risk for
their health integrity there's less worry about that phase, so there's a bit less aggressive
treatment.
Adherence Promotion Considerations :
- Patients may fail to acknowledge condition / Manic episodes described as ‘enjoyable’ by some ->
results in them not wanting to get medicated and they want to continue to live them so here
there might be difficult for adherence so discussion with the patient is to be expected.
Interprofessionnel with psychotherapist, physician, social workers etc. try to come with the best
agreement with the patient
- Short-term hospitalization sometimes warranted → Allows to monitor Lithium administration (
since therapeutic index is really narrow, so proper monitoring is needed)
- Patient Education + Social Support = Classic optimal SBN combination 
3.2.2- mood stabilisers:
Lithium:
What is lithium?
- one of the first line drugs for management of bipolar disorder.
It there in terms of Its pharmacology:
- lithium is only efficient at abortive and prevention
of manic episodes, it doesn't help with the
depressive phases of bipolar.
Efficacy only vs. Manic episodes
Uses: Abortive & Prevention
The mechanism of action: is still unknown.
- There are several hypotheses.
1) Modulates glutamate neurotransmission, which is the main excitatory
neurotransmitter, so it could reduce it, and by doing that reducing manic
episodes.
2) It could modulate G protein and cyclic AMP regulated pathways. Once again
kind of reducing their activity to reduce the intensity of a manic episode.
3) it could increase GABA concentration and act a lot like CNS depressant like
benzodiazepine.
- Data from animal studied
 its benefits would come mostly from neurotrophic and neuroprotective actions,
meaning that it protects existing neurons and promotes growth of new neurons
so potentially solidifying optimal connections between groups of neurons and
adjacent regions to foster a better at functioning pathways in the brain.
Mechanism of Action = Unknown!
Several Hypothesis:
1) Glutamate Modulation
2) Modulation of G-Protein & cAMP pathways
3) Increase GABA concentration
Data from animal studies:
Benefits from neurotrophic & neuroprotective actions
What we do know about it is have more about its kinetics:
-
Kinetics: Very short T
-
mind especially TI since it has a lot of toxicity soi t has to monitor very
closely, short life meaning that you would have to administer it
frequently throughout the day)
Administer PO in divided daily doses
Kidney excretion → Watch out for renal impairment & sodium levels
1/2
+ Very narrow TI ( very important to keep in
 KIDNEY: It's mostly excreted by the kidneys, so because of the narrow therapeutic
index, anybody with renal impairment or elevated sodium levels must be even more
closely monitored because that will influence the concentration.
Lithium- Toxicity and monitoring:
Keep level below 1.5 mEq/L
Optimal Range: ≈ 0.6-0.8 mEq/L
Individualise Dosage + Tight Monitoring
 The reason why we need to monitor so much again as indicated in the table here the
optimal range of lithium should be to try to shoot between .6 and .8 million
equivalents per liter and to keep it below 1.5.
 below 1.5, there are still significant signs of toxicity like nausea, vomiting, diarrhea,
lethargy, slurred speech, muscle weakness. So even below 1.5 there's a significant
toxicity.
 Above 2.5: symptoms may progress rapidly to generalized convulsion, oliguria, and
death. VERY VERY TOXIC NOT TO BE MESSED AROUND.
Adverse Effects at Therapeutic Level
• GI Disturbances: Common but transient
• Tremors: mitigate with β-blockers
• Polyuria: Antagonism of ADH → Must drink frequently!! ( because they will urinate frequently
regardless, so need to replenish the fluid)
• Renal Toxicity: Mostly with chronic lithium therapy
• Teratogen: Avoid during 1st trimester (only in 1st trimester and then it can be reenitated)
Noteworthy Drug Interactions
•
•
+
Diuretics: ↑ Na loss → Lithium accumulation (Loss of sodium means that lithium is conserved
to accommodate that, because lithium and sodium on the periodic table, are on the very far
left. So that when there's loss of sodium, the body will actually retain the lithium a lot more)
NSAIDs: ↑ Lithium renal reabsoprtion (except Aspirin) ( this can lead to inc in concentration
which in the table above leads to more toxicity)
Antiepileptic Drugs:
The other options besides lithium's are two anti-epileptic drugs which are valproic acid also
known as sodium valproate and carbamazepine.
Sodium valproate:
When sodium valproate compared to lithium valproate has pros and cons:
- PROS : so it's better in terms of onset and in terms of safety and in managing manic
symptoms.
- CONS: is that it has a higher rate of relapse and not as good in terms of suicide
prevention to reduce suicidal ideations as well as being completely ineffective, I know I
mentioned that lithium was not very good with depressive symptoms.
The main toxicities : to recall for valproate is really hepatotoxicity and teratogen.
- So in terms of toxicity profile, it's also it's clearly much safer. There's still some, but less
things to keep in mind, and also the therapeutic index is much larger compared to
Lithium.
Carbamazepine:
Carbamazapine >>>> inferior to valproate.
- There's some situations where it may be carbamazapine could be preferred, especially if
there is significant hepatotoxicity.
Main toxicities:
- are mild neurologic effects (common)
- severe hematologic effects (rare)
- many interactions with P-450 enzymes, which is really what complicates.
3.3.1 anxiety disorders management:
General consideration:
Best Therapy: combination of both
Psychotherapy (ex.: CBT) + Pharmacotherapy
1st-Line Drug Option = SSRIs (seretonin reuptake
inhibitirors)
Significant SBN Potential =
•
•
•
•
Healthy Lifestyle
Social Support (BEST ONE TO OVERCOME
FEAR AND ANXIETY)
Patient Education (
Foster Collaborative Relationship = Crucial!
General anxiety treatments:
Best therapy= CBT + DRUG
Long term management vs Rapid stabilization:
Options
Long-Term Management (SSRIs
and Buspirone)
Rapid Stabilization (benzodiazepines)
Preferred Drugs
SSRIs & Buspirone because they
have Delayed effects
Benzodiazepines it can offer a Rapid
relief
Notes
-
Best for cognitive &
psychic Sx
Low abuse potential
No interactions with CNS
depressants
-
Best for somatic Sx alleviation
Abuse Potential explains
declined use
Gradual tapering off = Crucial to
avoid withdrawal Sx
 somatic sx : felt within the body ( such as inc hr, sweating, muscle spasm becasue of
excessive sympathetic nervous system)
 cognitive and psychic symtpoms: related to internal thoughts process and the emtoions
felt.
Nondrug Tx: More details in Antidepressant Section
Ex.: Cognitive Behavior Therapy (CBT) / Support Groups / Physical Activity
Biofeedback / Mindfulness-Based Stress Reduction (MBSR)
 Use of biofeedback: which are devices that allow people to monitor their own
physiology, so an example of a biofeedback would be a device like a Fitbit.
 That tells you what your heart rate and your respiration rate is now. It gives you
feedback on your current biology and Physiology and what those can help with is
that they can teach patients individuals to regulate their own Physiology.
 Someone could be monitoring their own heart rate and then kind of associated
with their state of mind They can say OK, right now I feel really stressed and
anxious and my heart rate is I don't know like something like a 95- 100 etc
alright, I'll try to take some deep breaths and then they can actually see that
taking deep breaths or whatever intervention they're doing is helping them as
their heart rate decreases so it gives them feedback that whatever they're doing
is successful.
Panic disorder therapy:
1st-line Rx: SSRI Antidepressants :
- They can help dec ↓ anticipatory anxiety; avoidance behaviors;
frequency & intensity of attacks
- Transient rebound anxiety upon initiation → Start with low dose
 Transient rebound anxiety: There is a transient rebound anxiety upon initiation, so a lot
of patient education about that to advise and keep an eye out for that to expect it and
not be surprised and think that they're going into a panic attack and starting with the
lowest dose possible, can help to minimize this effect.
2nd-line Rx: TCAs ( tricyclic antidipressants) / MAOIs (monoamine oxidase) /
Benzodiazepines
- Efficient but less well tolerated vs. SSRIs ( effcient but more toxicity compared to
SSRIs)
Nondrug Tx:
- CBT ( cognitive behaviour therapy) & MBSR
(mindfullnes based stressed reduction) such as
meditation and breathing exercises.
- Avoid stimulants (ex.: Caffeine, Cocaine)
- Healthy Lifestyle ( such as proper sleep pattern,
healthy eating)
Obsessive – compulsive therapy:
Nondrug Tx: CBT
- Fear-control exercises (CBT) → Very
Efficient (ask to confront their fear
straight on and to try to exert control
over it to reverse, because a lot of the
problem here is that the fear and the
obsessive thoughts are controlling the
person and here it's about regaining
control)
- Deep brain stimulation for severe cases
(analogous to the electoral convulsive
therapy)
Pharmacotherapy :
1st-line Rx: SSRI Antidepressants
- Benefits via ↑ 5-HT
transmission
- Delayed onset
- Continue Tx for at leat 1 year
For social anxiety therapy:
Nondrug Tx: CBT
- Gradual social exposure exercises (CBT) → Very
Efficient (In the sense that you, the person, is
exposed to social situations in an incremental
manner, so they can be introduced to a single
person at a time then they have to talk with a
complete stranger then it's two or three people at a
time then it's a bigger crowd, so on and so forth. So
it helps them get more comfortable and gain
confidence in their social abilities)
Pharmacotherapy :
1st-line Rx: SSRI Antidepressants
- Delayed onset ≈ 4 weeks
- Very useful for patients
obliged to face frequent
anxiety-provoking situation
2nd-line Rx: Benzodiazepines & β-blockers
- Rapid onset
- Useful for performance anxiety (ex.: stage
fright)
 2 ND LINE benzodiazepine's and beta blockers due to rapid onset can help, especially
with the case of performance anxiety. So individuals that have for example stage fright
or I have to do a public speech and they have fear of public speaking etc using those
drugs prior can help stabilize their heart rate. So that their hands are not shaking their,
their voice is more in control, but this should be a temporary solution in the sense that it
can help with you know a specific situation coming up and that they don't have time to
prepare for that Very much, but then after that they should still investigate the issue
and work on Strengthening their resiliency and comfort level with social context so that
they don't have to rely on that for the rest of their lives.
PTSD therapy:
3 core Sx (symptoms of PTSD) :
1)Re-experiencing the event
2) Avoiding reminders
3) Hyperarousal / hyper vigilance
Nondrug Tx: Specific CBT Techniques (respond well to
it)
1) Trauma-focus exposure Therapy:
Reimagining events until they lose their power
2) Stress Innoculation Training:
Teach coping skills against fear-provoking cues
 once again here it's a matter of control where unfortunately, the traumatic experience
has immense power over that person. The stress that it causes when the person reexperiences the event or when they see a reminder and then it triggers memories once
again.
 So, the idea here is to practice impact to try to empower the person to regain control
over their traumatic experience so that now they're the one in control they have power
over it that rather than the other way around.
Pharmacological Options:
- 1st-line Rx = SSRI Antidepressants
- 2nd-line Rx = Mirtazapine; TCAs or MAOIs
No evidence for:
- Buspirone; Buproprion & Benzodiazepines ( These drugs are advised but theres no evidence that
it works for PTSD)
Promising New Evidence:
- MDMA & Psychedelics-assited Psychotherapy (That is currently under investigation with by the
FDA for breakthrough therapy in the sense that they have been shown to have low toxicity and
high promises of efficacy for PTSD management)
- More details in drugs of abuse section
3.4.1- basic considerattions
Basic considerations:
 Antidepressants probably one of the class of drugs that get the most public and media
coverage. Basically, because depression is such a common ailment in society and the
medicalization of it is clearly a topic with a lot of social stigma and everybody has an
opinion.
Antidepressant:
Disputed efficacy: (media coverage come from this)
 Clear benefits only for severe depression (but for mild and even to moderate
depression, it's unclear if the drugs are beneficial or even efficient)
 Strong Placebo Component (To the efficacy of those drugs, but also to just the
pathology of depression, which is multifaceted and there's many things, including the
behaviors and the thought process of the individuals that has an influence on if they feel
better a particular day or not)
 Adaptive neuronal changes > Enhanced Neurotransmission (
 Its become clear that whatever benefits that drugs have come from more from
the adaptive neuronal changes that they induce rather than the exact enhanced
neurotransmission.
 So for example, the SSRI is the infamous antidepressant class of drugs that
increase the amount of serotonin in the brain, it seems like what is actually
beneficial is not so much that they increase the amount of serotonin in the brain,
but that the increase in serotonin in the brain forces the brain to readjust its
pathways and to reconstruct neuron connection. And it's those reconstructions

that would then lead to a more appropriate thought process and better well
being.
So that could explain also the one of the facets of those drugs which have a very
important delayed therapeutic response.
Delayed therapeutic response:
 Initial effects: ≈ 1-3 weeks (Even though the increase in serotonin is fast, it's because it
takes that much time for the neuron connections to be reorganized.)
 Full effects: ≈ 12 weeks
 Should try for at least 1 month (The full effects only come into action about two to
three months later, so that the drugs should be tried for at least a month before
considering that it doesn't work for a particular patient)
 Do not administer PRN (It should be like a more thoughtful and intentional regimen, and
not to be taken just as needed but for the purpose of reorganizing neuronal
connections)
Drug selection based on safety profile:
- New agents (SSRIs) safer than Older agents (TCAs & MAOIs) (In terms of drug selection,
it should be based on safety profile because the efficacy between all the antidepressant
classes seems to be pretty much on par so that we should choose the agents that are
safer and the reason the SSRIs is are so famous it's because they are safer compared to
the other options)
- Pair patient with potential beneficial side effect
 Ex.: Patient with sexual dysfunction → Buproprion ↑ libido (So, for example,
bupropion is known to have a side effect of increasing libido, but that certain
patients suffering from depression have suffered from sexual dysfunction so that
could be a good pairing where a side effect becomes an extra therapeutic
effects)
Managing treatments:
- Start low dose & increase gradually
- Switch Rx if inefficient after 4-8 weeks
- Tx for 4-9 months minimum
- Taper off gradually over several weeks
Meta-analysis:
- try to figure out among all the antidepressants are there a few or one that is much
better than the others, and what they found is that even though most antidepressants
were more efficient than placebo and adults, the summary effect size were mostly
modest. ( they work but not much better than placebo)
- interestingly, was that fluoxetine, which is a SSRI, was the only efficient option for
minors.
 difference between drug is low between all
They were able to make a ranking here.
 For the most tolerated column, because they also compared the antidepressants for
safety purposes. And clearly what you see here is that the SSRI's are the winners.
 terms of efficacy seems like the classes are similar, but for safety, SSRIs is our best
 the best one for reducing symptoms of depression is amitriptyline but it has a lot of side
effects.
 The other best one is agomelatine which is most efficient and most tolerated.
Suicide risk and antidepressants:
Safety Alert: ↑ Suicide risk
All Antidepressants
Apply mostly to patients under 25
 Many antidepressants have a safety alert on their box reporting an increase in suicide
risk.
So this brought up this question:
Should Antidepressants be discontinued??
Probably not :
- Suicide risk of untreated depression >
Antidepressant Rx suicide risk
(probably not because the suicide risk of
untreated depression is actually greater
than the risk induced by the drug itself)
- Hospitalization = Best option if risk ↑↑(
this can allow for more supervision)
 Table: So what you can see from the table here: you look at major depression studies
versus all pathologies, you can see that there's not that much a difference. Which
means that usage of drugs for treatment of depression then induce much change
compared to individuals that had another disease, so it's possible that the suicide risk
only came from the fact that the person had a pathology whatsoever, regardless of what
it was.
Mitigation Strategies :
- Frequent follow-ups with medical team
- Daily monitoring by family members
- Watch for rapid Sx deterioration
- Prescribe small amounts at a time
- Watch out for ‘cheeking’ (hide meds in the cheek to
pretend they swallowed it but they didnt)
Peripartum depression:
 There is also peripartum depression, which is any forms of depression around the
around the delivery of a baby.
Table:
- Compares it to baby Blues to show that peripartum depression is not just baby Blues, t's
a lot more than that.
- Peripartum depression:
 It should be treated like a major depressive episode.
 It lasts much longer
 The prevalence is much less
 The severity is moderate to severe.
 And suicidal ideation may be present
 it's called peripartum depression, not postpartum, because we now know that
it can start even before the delivery, even before the baby is born.
 Therapy with SSRIs should be favored.
Selective serotonin reuptake inhibitors (SSRIs)
SSRI stands for: selective serotonin reuptake inhibitor
SNRIs
Block Norepinephrine + Serotonin
Similar Efficacy & Adverse Effects
Inferior Tolerability
How does the drug work?
- They inhibit the reuptake protein on at the neuron synapse, so that the serotonin that is
released by this particular neuron will remain within the synapse for longer which
means that they will activate this subsequent neurons receptor more for longer period
of time more frequently.
- So overall it increases serotonin transmission by preventing the reuptake of the
serotonin into the initial neuron.
There is also another class of drug called the SNRI:
- which acts the same way, but it's not selective to serotonin because it blocks also
norepinephrine in the same fashion.
- It has a similar efficacy, but because it's less selective it tends to have more adverse
effects, so it has inferior tolerability on average.
There's quite a few options of drugs:
- Prozac , Zoloft -> very famous drugs and they're often thrown out there and in media
and songs and movies and shows etc.
- I was told by several faculty and students of ice on that in at least in the Montreal
hospitals and clinics, telegram tends to be the most popular SSRI administered.
 You can see also that their SSRS are approved for many indications major depression but
also obsessive compulsive disorder, panic disorder, social phobia general anxiety, PTSD
and so on and so forth.
But based on the meta analysis shown earlier: ( in green)
- Escitalopram and paroxetine seemed to be a slightly superior options compared to the
others, but it's not being very significant.
Major ADRs and interactions:
Sexual Dysfunctions
Very common!! 70% of cases (one of the mahor
cause of non adherance with pt)
Management: Drug ‘holidays’ & dose ↓
Underreported → Patient education
Weight Gain
↓ sensitivity of appetite-regulating 5-HT receptors
Serotonin Syndrome (serious and can
happen in the early initiation of regimen)
Onset: 2-72h post-initiation
Sx: Altered mental states; sweating; fever; tremors
Can be fatal → Discontinue Rx ASAP!
Withdrawal Syndrome
Taper off gradually ( usually doesnt happen cause
theyre on this drug for a long time)
Neonatal Effects (Teratogen, but mostly
towards the end of pregnancy and effects will
be observed in the newborn, so it's important
to keep ventilatory support and close
monitoring if there is a treatment, especially
for peripartum depression)
Neonatal abstinence syndrome: Respiratory distress
& seizures
Persistent pulmonary hypertension of newborn: Risk
of death or cognitive impairment → Ventilatory
support + close monitoring
Interactions
MAOIs → ↑ 5-HT levels → ↑ 5-HT syndrome risk
SSRIs ↑ TCA & Lithium concentrations
Antiplatelet & Anticoagulants: ↑bleeding risks
Tricyclic antidepressants (TCAs) :
Tricyclic antidepressants or TCAs: work in a very similar way to the SSRI's, but they lack this
selectivity so they inhibit the reuptake of many neurotransmitters.
so you can see in the diagram here:
- that they do block the Serotonin reuptake, but also noradrenaline.
- Which means that they'll have activity at adrenergic receptors -> Side effect orthostatic
hypotension
- they also block histamine receptors -> side effect sedation
- as well as block muscarnic ach receptors -> side effect anticholinergic symptoms and
cardiac toxicity
- major toxicity : which includes orthostatic hypotension, sedation and anticholinergic
symptoms or even cardiac effects due to muscarinic receptors located on the heart. So a
lot of that toxicity is similar to the antipsychotic drugs due to those effects.
Examples of TCAs:
- The best examples of TCS include Amitriptyline and Mirtazapine, which are two of the
most efficient antidepressants in terms of reducing symptoms but their toxicity makes
them a second line drug instead
Amitriptyline and mirtazapine therapeutic use
- Major depression: 2nd line drugs
- drugs that are used for other conditions as well, especially for management of
Neuropathic pain, they seem to be quite efficient at that, so they're among the favorite
drugs for those conditions
- as well As for fibromyalgia, which doesn't have a lot of therapeutic options they're one
of the few drugs that can help with that.
Therapeutic Uses
nd
Major Depression: 2 -line Rx
Neuropathic Pain
Fibromyalgia
Important interactions:
Important Interactions
- MAOIs → Severe Hypertension
- Sympathomimetic & Anticholinergic Rx
- Other sedatives (ex.: alcohol, opioids)-> Overdose risk (TI ≈8)
MAOIs: Action and use:
Third class of antidepressant drugs to mention are the monoamine oxidase inhibitors or MAOIs.
Monoamine Oxidase A inactivates NE & 5-HT → Inhibition = Antidepressive effect
Monoamine Oxidase B inactivates DA → Inhibition = Antiparkinson effect
How does it work:
- They block the enzyme MAO and the job of this enzyme is to actually change or
metabolize neurotransmitters into inactive products within the neuron following the
reuptake.
- But by blocking this enzyme, what happens that then the neurotransmitters remain
active in their active form so they're put back into vesicles, and then they're released
following the next neuron activation.
- So once again It's an indirect way to increase the amount of neurotransmitters within
the synapse. it's not selective to a particular type of neurotransmitter, so they do have
more toxicity compared to the SSRI's, for example.
Therapeutic use:
Atypical Depression = depression with 1
Therapeutic Uses
nd
-
rd
Major Depression: 2 /3 -line Rx behind
SSRIs and TCAs
Atypical Depression: 1st choice Rx
exception:
Mood is elevated in response to positive
events (so it's individuals that don't have
the anodynia the inability to experience
positive emotions even when they have
good news, so individuals with atypical
depression when they receive good news,
they might feel good, but then they will
quickly go back into a more depressive
mood, and unless they have another good
news, they will remain into that state.)
MAOIs = best choice of drug for this situ
There are two forms of the monoamine oxidase enzyme:
Monoamine Oxidase A inactivates NE & 5-HT → Inhibition = Antidepressive effect
Monoamine Oxidase B inactivates DA → Inhibition = Antiparkinson effect
 Inactivation of form A would lead to an increase in norepinephrine and serotonin which
that would lead to antidepressive effects
 Inhabition of oxidase B form would lead to an increase in dopamine and that would lead
to antiParkinson effect and that's why there are also MAOIs used for treatment of
Parkinson disease because it targets more the MAOB form.
MAOIs: adverse effects:
Their toxicity profile is inferior to the others that's why it's not a first line drug for major
depression.
Hypertensive Crisis
Severe Hypertension
Stroke
One of the big concerns is known as hypertensive crisis:
- that can lead to severe hypertension and stroke.
How does the hypertensive crisis work?
- The way it works is that tyramine is one of the Amino acid that we get from food that is
a precursor to norepinephrine and normally when we get it from our diet it goes
through the liver and it gets metabolised into inactive form so that not that many
become norepinephrine. Right, so that there's more control over the amount of
norepinephrine released by the sympathetic nervous system.
- But MAO inhibitors block this pathway so that the tyramine from our diet directly goes
into our neurons and it increases the amount of norepinephrine release whenever there
is sympathetic activation. Remember that sympathetic nervous system increases the
heart rate increases stroke volume. Things like that, so that's why it can lead to a
hypertensive crisis like an excessive activity of the sympathetic nervous system with
the use.
Hypertensive crisis and food:
-
it's more likely, when combined with food that are rich wine and cheese.
You can see that many milk products is practically all cheeses as well as certain wines
like Chianti, wine or foods with yeast that are commonly combined at certain events, so
it actually wasn't unlikely to observe certain individuals on MAOIs unaware of that effect
going to a wine and cheese, taking a few pieces of cheese, a glass of wine, and then they
would have severe hypertension stroke and maybe a cardiovascular event on the spot,
Other noteworthy toxicities:
Other noteworthy toxicities
↑ NE in CNS → ↓ Sympathetic firing → Orthostatic Hypotensions
Many Drug Interactions → Avoid all Rx unless also prescribed
Ex.: SSRIs / TCAs / Antihypertensive Rx (antihypertensive : these one
cancel their beneficial effect)
 If it's in the PNS that there's an extra tyramine extra norepinephrine That's when we
get the hypertensive crisis because sympathetic nervous system goes to the periphery.
 But if it happens in the CNS, then it has an opposite effect on the sympathetic nervous
system and then you get hypotension instead.
Atypical antidepressants:
Agomelatine :
Action: Melatonin Agonist + 5-HT Antagonist
- Positive mechanism is that Melatonin action
normalises sleep cycle
- 5-HT antagonism ↑ DA & NE release in frontal
lobe ( so not an antagonist everywhere)
- They would Called ‘DA-NE disinhibitor’
Toxicity: Very well tolerated
- Potentially less toxic than other Antidepressants
- Possible hepatotoxicity → Monitor ALT & AST
- Sleep disturbances & Nightmares due to the
melatonin
Mirtazapine
- Grouped under TCAs
- Antidepressant effects ( comes from
reuptake inhibition of seratonin) = SSRI &
faster onset ( faster onnset than SSRIs thats
why it can be used for certain acute
episodes)
Action:
- Blockade of presynaptic α2-receptors -> ↑
5-HT & NE release
Toxicity: Well tolerated
- Histamine block → Sedation + Weight gain
- CNS depressant & MAOIs (avoid this
combo) ↑ sedative effect
Unfortunately not approved by FDA & Health
Canada yet even though it is listed as a first line
drug in the Canadian Guidelines…
3.4.4 Alternative therapies for depression or other mental illnesses
Dietary supplements:
Limited efficacy or insufficient evidence to claim anything
S-Adenosylmethionine (SAMe):
- Evidence suggest Superior to TCAs & improved Sx in
SSRI-resistant patients
- Mechanism: ↑ synthesis of NE, 5-HT & DA in CNS
but limited evidence
St-John’s Wort:
- Superior to placebo for mild-moderate depression
not good for severe depression
- Unclear mechanism of action
- It can induce toxicity such as P450 & P-glycoprotein
inducer
Electroconvulsive therapy: (ECT) a lot of controversy
How does it work?
How does it work??
- Produce generalized seizure for 20-30sec to ‘reset the brain’(Remember how I said that most of
the antidepressants: It seems like the beneficial effects is not because they increase the amount
of certain transmitters, but it's because it forces the brain to reorganize well. The idea here is the
same is that the electroshocks and the seizures would force the brain to reorganize)
- Requires 6-12 treatments for a whole regimen
- They administer Short-acting muscle relaxant & IV anaesthetic for safety
- Consciousness unnecessary for benefits!!
Adverse effect:
Adverse Effects?
- Rare but possible
- Transient Amnesia ( extremely rare)
- Cognitive Impairment
Does it work?
Relatively Safe + Fast Benefits (main advantage no delayed onset i tacts much faster)
- 8% relapse with ECT vs. 73% without (The relapse rate, meaning the onset of
depression in the future, was only 8% with those that underwent a course of
ECT, whereas it was 73% for those that didn't go through ECT. So it seems quite
effective, or at least the relapse rate indicates as such)
Who should get ECT?
Who should get ECT?
Severe depression unresponsive to Rx
 IF UNRESPONSIVE TO OTHER DRUGS
Other therapies:
 There are many other therapies that are kind of trying to go in that vein, but
unfortunately the evidence is not as clear ECT for the benefits.
1) Transcranial magnetic stimulation: disputed evidence (idea is the same as ECT but no
strong evidence)
2) Vagus stimulation:
 Developed as an anti-seizure Tx
 Unclear evidence
 Very costly: ≈25,000$/year
3) Light therapy: safer and cost effective option (efficient for seasonal depression)
 ↑ 5-HT Transmission
 Response ∝ to light intensity
 Low cost & risk
Nothing beats healthy lifestyle:
 One of the most efficient antidepressant intervention is exercise. There is tons of
exercise evidence that suggests that exercise is actually more efficient than any drugs
against depressive symptoms.
 another one would be meditation, especially probably via the reduction in activity of
the default mode network which is associated with increased sense of control and less
rumination two things, the perceived control is something that is known to protect
against depressive symptoms, and rumination is something that we know it's quite
common in individuals suffering from depression where they get trapped into a vicious
cycle of thoughts, and then they have difficulty getting out of it. Practicing meditation
helps someone feel like they're more in control of their thoughts and they can self
distance and not identify with them as much. Practicing that has been shown to
alleviate symptoms of depression, and if you wonder in the graph below here it shows
how meditators had less activity and less symptoms of depression compared to controls
and the different colors only indicate different forms of meditation.
Drugs of abuse under scrutinity:
 there's novel therapies, drugs that are considered drug of abuse with no medical
purposes are actually being studied right now. There's a lot of interest in them,
especially ketamin, psychedelics like magic mushrooms psilocybin, Al Waska ?? as well
as MDMA ecstasy for reappropriating their use for medical purposes in the sense that
they could have a lot of beneficial effects for mental illnesses that are resistant to
treatment.
 where the FDA called Psychedelic for breakthrough therapy for severe depression
ketamine as well and it's not just for depression, it's also for PTSD, for addiction, for
severe anxiety disorders.