Psychoanalytic /

Psychodynamic

Therapy

theory:exploration of meaning of early experiences Psychologically minded,highly

motivated,wish lo understand selves

Time intensive:

Psychoanalysis: 4-5 times/wk lor 3-7 yr

Psychodynamically oriented therapy:

2-3 times/wk for fewer yr

depression and not just relieve symptoms

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PS51 Psychiatry Toronto Notes 2023

Pharmacotherapy

Dopamine Pathways Affected by

Antipsychotks Antipsychotics

Pathway Effects Associated

Pathology

•

“antipsychotics" used to be called “neuroleptics”

•overall mechanism of action: functionally antagonize, to varying degrees, D2 activity in target brain

pathways

•primarily indicated for psychotic symptoms in:schizophrenia and related disorders, manic episodes,

depressive episodes,substance use, medical conditions (e.g. neoplasm)

•other uses:treatment-resistant MDD,severe GAD, complex PTSD,severe OCD, borderline PD,

behaviouralsymptoms of dementia,delirium,

'

l

'

ourette syndrome,substance use disorder in dual

diagnosis, Huntington s disease, ASD, and impulse control disorders

adjunctive management of agitation, aggression,severe anxiety, and severe sleep difficulties when

sedative-hypnotics are contraindicated

•onset: acute, rapid calming effect and decrease in agitation;antipsychotic effect with improvement in

thought disorder, delusions, and hallucinations may take 1-4 wk

•rational use

• no reason to combine two or more antipsychotics, although thisis quite common in clinical

practice

all antipsychotics are equally effective, except for clozapine (considered to be most effective in

treatment-resistant schizophrenia)

atypical antipsychotics (i.e. second generation) are as effective as typical (i.e.first generation)

antipsychotics and have different adverse effect profiles; main difference islower risk of EPS and

TD but more metabolic side effects (see sidebar)

choose a drug to which the patient has responded to in the past or that was used successfully in a

family member

•route: PC),short-acting or long-acting depot IM injections, and sublingual; more recently there is

inhaled loxapine mainly used in the setting of acute agitation

•if no response in 4-6 wk,switch drugs

•duration: minimum 6 mo and usually forlife in most patients with primary psychotic disorders;

variable for other indications

Mesolimbic Emotion HIGH dopamine

origination, causes positive

reward symptoms ol

schiiophrenia

(delusions,

hallucinations)

Mesocortkal Cognition, LOWdopamine

executive causes

function negative

symptoms of

schiiophrenia

Nigrostriatal Movement 10W dopamine

causes EPS

LOWdopamine

causes hyperprolactinemia

Tubero- Prolactin

infundibular hormone

release

Typical (first Generation) vs.Atypical

(Second Generation) Antipsychotics

Typical Atypical

Mechanism Block Block

postsynaptlc postsynaptic

dopamine dopamine

receptors(D2) receptors(02)

Block serotonin

receptors(5-HT2)

on presynaptic

dopaminergic

terminals,

triggering DA

release,and

reversing 0A

blockade in some

pathways.Some

are partial 02

agonists

Long-Acting Preparations

•antipsychotics formulated in oil for IM injection

•received on an outpatient basis

•indications:initially meant for individuals with schizophrenia or other chronic psychosis who relapse

because of non-adherence,but current initial evidence suggests they are better than oral preparations

overall

•should have been exposed to oral form prior to first injection

•dosing:start at low dosages, then titrate every 2-4 wk to maximize safety and minimize side effects

•side effects:similar to side effect profile to oral preparation of the same drug

Canadian Guidelines for the Treatment of Acute Psychosis in the Emergency Setting

•haloperidol 5 mg IM ± lorazepam 2 mg IM

•loxapine PO or IM 25 mg ± lorazepam 2 mg IM

•olanzapine 2.5-10 mg (PO, IM, oral quick dissolve -it’

s time to peak is the same as regular PO, 4-6 hr)

•risperidone 2 mg (M-tab, liquid)

Inexpensive EPS less prevalent

Plenty ol low-risk

injectable ol tardive

lotms

available

Pros

syndromes

Mood stabilizing

effects

Cons EPS more

prevalent,

including

tardive

syndromes side effects

in long-term (weight gain.

Hot mood

stabilizing

Expensive

Fewinjectable

lorms available

Metabolic

hyperglycemia.

abnormalities.

metabolic

syndrome)

Exacerbation

(or new onset)

olobsessive

behaviour

Anticholinergic Effects

Red asa beet

Hot asa hare

Dry asa bone

Blind asa bat +

Mad asa hatter

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PS52 Psychiatry Toronto Notes 2023

Table 15. Common Antipsychotic Agents

Starting Dose Maintenance Maximum Relative Potency (mg)

See landmark Psychiatry Trials table lor more

information onMilt,which details a comparison

b elween first and second-generation antipsychotics

m the treatmentof sdnroplirenia.

Typicals (in order olpotency Iromhigh tolow)

Haloperidol (Haldol!

) 2 5 mg IM q4-8 h

0.5-5 mg PO B/TIO

0.2mg/kg/d PO

Fluphenaiine enanthate 2.5-10 mgfd PO

(Moditen '

.Modecate (or

IM formulation)

Zudopenlhixol HCI

(Clopixol-)

Zudopenthixo! acetate 50-150 mg IM q48-72 h

(Acuphase3)

Zuclopenthixol decanoale 100 mg IM q1-4 wk

(Cloxipol Depot'

)

Perplsenaiinc (Irilafon '

) 8 16 mqP0 8/IID

Lonapme HCI (Loxitane ) 10 mg P01ID

12.5-50 mg IM q4-6 h

10-25mgP0 Bl/ /0ID

Based on clinical effect 20 mgfd PO 2

1-5 mg PO OHS 20 mg/d PO 2

25 mg IM/SC q1- 3 wk

Metabolic and Cardiovascular Adverse thesis

Associated with Antipsychotic Drugs

N at Rev Endocrinol 2012:8:114-126

All atypical antipsytbobts can cause cardiovascular

and metabolic side effects,such as obesity,

dyslipidemia.hyperglycemia, and vreightgain.

Olanrapme anddoupme are most likely to cause

these adverse effects.Ihe medianism that nnderkes

the metabolic and cardiovascular effects is notInly

understood.However,the histamine,dopamine,

serotonin,and muscarinic receptors areimplicated.

20-30 mg/d PO 20- 40 mg/d PO 100 mg/d PO 4

400 mg IM (q2 wk)

150-300 mg IM q2 wk 600 mgIM/wk

4 8 mgPO T/OID

60-100 mg/d PO

64 mg/d PO

250 mg/d PO

TO

10

Chlorpromazlne

(Largactil :

)

400 mg/d PO 1000 mgfd PO 100

Atypicals (in order ol potency fromhigh lolow)

Risperidone (Risperdal 1

, 12 mg once daily/BID

Risperdal Consta'

lor IM

long acting preparation.

Risperdal 1 M-Tab lor

melting form - placed on

tongue)

Paliperidone (Invega'

. 3mgfdP0

Invega Sustenna

’

lone

v) orTrima'

(three

months) forIM long acting

preparalions)

OTc prolongation is an important adverse

effect of all antipsycholics; although not

required,consider getting ECG prior to

and after initiating new medication and

to monitor OTc

Typicals:chlorpromazine and

haloperidol warrant systematic baseline

and follow up ECG

Atypicals: ziprasidone has the highest

risk among atypicals, clozapine also

warrants systematic baseline and

follow-up ECG

4 8 mg/dP0

25 mglMq2 wk

8 mg/d P0 2

3-12 mg/d P0 12 mgfd P0 4

Olanzapine (Zyprexa 3, 5 mg/dPO 10-20 mg/dPO 30 mg/d P0

Zyprexa Zydrs '

lor melting

form - placed on tongue)

Asenapinc (Saphris

’

) 5 mg $1BID

20 mg P0 BIO

10-15 mg/dPO

25 mg PO BID

5

5-10 mgSt BID

40 -80 mg PO BID

10-15 mgfd P0

400-800 mg/dPO

10 mg St BID

160 mg/d P0

30 mg/d P0

800 mg/d P0

5 Features ol Neuroleptic Malignant

Syndrome Ziprasidone (Zeldox

’

)

Aripipraiole(Ability 9)

Ouetiapine (Seroquel -.

Seroqnel XR!

for extended

release 3 }

Clozapine (Clozaril ' ) 25 mgP0 BIO

6

7.5 FARM

Fever

Autonomic changes (e.g. increased

HR/BP,sweating)

Rigidity of muscles

Mental status changes (e.g.

confusion)

75

300 600 mgfd P0 900 mq/d P0 100

FARM symptoms are also seen in

serotonin syndrome (SS)

SS can be distinguished from NMS by

the following:

SS NMS

Twilchy. shivering, Severe globalrigidity

restless

Flushed,sweaty Pallor

Vomiting,diarrhea. No Gl symptoms

abdominal pain

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PS53 Psychiatry Toronto Notes 2023

Table 16. Commonly Used Atypical Antipsychotics

Olanzapine

(Zyprexa .

Zydis’

l

Ouetiapine

(Seroquel )

Clozapine

(Clozaril )

Aripiprazole

(Ability )

Risperidone

(Risperdal )/

Paliperidone

(Invega )

Most cltective for

treatment-resistant

schizophrenia

Docs not worsen

tardive symptoms:

may (real them

Approximately 50%

of patients benefit,

especially paranoid

patients and those

with onset after 20 yr

Lower incidence Better overall

of EPS than typical efficacy compared to slightly less weight

antipsychotics at haloperidol gain compared

lower doses(«8 mg) Well tolerated to clozapine and

Associated with less Low incidence of EPS olanzapine, but

weight gain compared and ID more than the other

to clozapine and atypicals

olanzapine Mood stabilizing

Advantages Associated with less weight gain

and risk of metabolic

syndrome compared

toolanzapineand

a lower incidence

olEPS compared to

haloperidol

Mood stabilizing

Disadvantages

Relative toOther

SGAs

Highest risk of EPS/ID Weight gain and

among SGAs - avoid metabolic effectsil high - risk for EPS or avoid in DM

existing movement Sedating - avoid if

disorder or elderly high -risk for fallsor

Elevated prolactin - fracture

sexual dysfunction,

galactorrhea.

gynecomastia.

menstrual

disturbance.

infertility

Sedating/orthostatic Weight gain and

hypotension - avoid metabolic effectsif high - risk for falls or avoid m DM

fracture

DT prolongation in

high doses- caution high -risk for fallsor

If cardiac risk

Insomnia,akathisia

Sedalingforthostatic

hypotension - avoid if

fracture

Potentially severe

constipation - avoid if

risk of fecal impaction

or bowel perforation

Cardiomyopathy -

caution if existing

heart disease

Reducesseizure

threshold - caution il

seizure disorder

Agranulocytosis

(1%) - avoid in

existing leukopenia/

neutropenia,

requires ongoing CBC

monitoring

Ouick dissolve

formulation (Eydis )

used commonly in

ER setting for better

compliance (but does

notactlaslcr)

Acute IM form

available

Comments Ouick dissolve

IM -tabs).and long

acting (Consta 3/

Invega Irinza - )

formulations

available

Weekly blood counts

for 6 mo. Ihenq2 wk

Do not use with

other drugs that

may cause bone

marrow suppression

due to risk of

agranulocytosis

Note: Risk o!weight gain:Clozapine > Olanzapine*Ouetiapine > Risperidone

Table 17. Side Effects of Antipsychotics

System Side Effects

Dry mouth, urinary retention, constipation, blurred vision, confusionalslates

Orthostatic hypotension, erectile dysfunction,failure toeiaculate

Extrapyramidal syndromes, galactorrhea, amenorrhea, erectile dysfunction, weight gain

Sedation, weight gam

Agranulocytosis (clozapine)

liver dysfunction, blood dyscrasias. skin rashes,neuroleptic malignant syndrome, altered temperature

regulation (hypothermia or hyperthermia)

Metabolic syndrome

OT prolongation

Anticholinergic

a-adrenergic Blockade

Dopaminergic Blockade

Anti-Histamine

Hematologic

Hypersensitivity Reactions

Endocrine

Cardiac

Neuroleptic Malignant Syndrome

• psychiatric emergency

• hypothesis: due to strong DA blockade; increased incidence with high potency and depot

antipsychotics

• risk factors

medication factors:sudden increase in dosage, starting a new drug

• patient factors: medical illness, dehydration, exhaustion, poor nutrition, external heat load, male,

young adults

• clinical features

tetrad: mental status changes (usually occur first), fever, rigidity, autonomic instability

• develops over 24-72 h

• labs: increased creatine phosphokinase, leukocytosis, myoglobinuria

• treatment:supportive - discontinue antipsychotic drug, hydration, cooling blankets, dantrolene

(hvdantoin derivative, used as a muscle relaxant), bromocriptine (DA agonist)

• mortality: 5%

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PS51 Psychiatry Toronto Notes 2023

Extrapyramidal Symptoms

• incidence related to increased dose and potency

• acute (early-onset; reversible) vs. tardive (late-onset; often irreversible)

Table 18. Extrapyramidal Symptoms

Dystonia Akathisia Parkinsonism Dyskinesia

Both Both Acute tardive

Older patients

Acute or Tardive

High-Risk Groups Acute:young Asian and Older females Older females

Black males

Presentation Sustained abnormal tremor;rigidity

posture:torsions,twisting, crawling sensation in legs (cogwheeling):akinesia:

contraction of muscle relieved by walking: very postural instability

distressing,increased (dccrcascd/absent armrisk of suicide and poor swing, stooped posture.

shuffling gait,difficulty

pivoting)

Acute:within 30 d

Purposeless, involuntary,

constant movements

that involve facial and

mouth musculature:less

commonly -the limbs:

rarely, the diaphragm

("hiccups”)

Tardive:>90 d.more

commonly yr

tardive:no good

treatment:may try

clozapine:discontinue

drug or reduce dosage

Recently the FOA

approved valbenazine

and deutetrabenazinefor

the treatment oltardive

dyskinesia

Motor restlessness;

groups; muscle spasms

(l.e.oculogyric crisis,

laryngospasm. torticollis) adherence

Onset Acute:within 5 d

tardive: »90 d

Acute: benztropine

or diphenhydramine,

usually IM

Acute:within10 d

tardive: >90 d

Acute:lorazcpam,

propranolol,benztropine, reduce dosage or

or diphenhydramine:best change antipsychotic

approach:reduce dose or to low potency atypical

change antipsychotic to antipsychotic

lower potency

Treatment Acute:benztropine:

Anticholinergic Agents

• types

• benztropine (Cogentin*) 2 mg PO, IM, or IV once daily (1-6 mg)

• diphenhydramine (Benadryl*) 25-50 mg PO/IM Qll)

• do not routinely prescribe with antipsychotics

give anticholinergic agents only if at high-risk for acute EPS or if acute EPS develops

• do not give these for tardive syndromes because they worsen the condition

Antidepressants

• onset of effect

relief of neuro-vegetative/phvsical symptoms:1-3svk

relief of emotional/cognitive symptoms: 2-6 wk

• tapering of most antidepressants is usually required to avoid withdrawal reactions:speed of taper

is based on the medication’

s half-life and the patient’s Individual sensitivity (i.e. fluoxetine does

not require a taper due to its long half-life; paroxetine and venlafaxine require a slower taper than

sertraline or citalopram)

• must be vigilant over the first 2 wk of therapy:neuro-vegetative symptoms may start to resolve while

emotional and cognitive symptoms may not (patients may be at risk for suicidal behaviour during this

time, particularly in children/adolescents)

• treatment of bipolar depression

• patients with bipolar disorder ( bipolar depression) should not be treated with an antidepressant as the

first-line therapy

patients with bipolar disorder should only be treated with an antidepressant if combined with

a mood stabilizer or antipsychotic; monotherapy with antidepressants is not advisable as the

depression can switch to mania

maintenance of patients with bipolar disorder with antidepressants is not advisable except in

specific cases

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PS55 Psychiatry Toronto Notes 2023

Table 19. Common Antidepressants

Class Daily Starting Dose

|mg)'

Drug Therapeutic Dose Comments

(mg)

SSRI fluoxetine (Proaac 20 80 *

)

lluvoxarnine (Luvox |

paroxetine (Paxil ')

sertraline (Zololl 3

)

citalopram (Celexa -*)

escitalopram (Cipralex 1)

20 Useful lor typical and atypical depression, seasonal depression, anxiety

disorders. 0C0.eating disorders

All SSRIs have similar effectiveness bul consider side effect profiles and hall lives

Citalopram and escitalopiam have the fewest drug interactions and ate sleep

v/ake neutral

Sertraline is the safest SSRI in pregnancy and breastfeeding

fluoxetine is the most activating SSRI(recommend takingin the AM)

Fluoxetine does not require a taper due to long half-life and is themost used in

children and adolescents as it has most evidence

fluvoxainlno is sedating (should be taken in PM) and can be involved in many

drug drug Interactions

For OCD,aim for maximum doses, sometimes higher

Useful for depression,anxiety disorders,neuropathic pain

50 100 150300

10 20 60

SO 50 200

20 20-40

10 10 -20

venlafaxinc ((flexor 3)

desvenfafaxine (Pristiq :

)

duloxetine (Cymballa :

)

bupropion(Wellbutrin -)

37.5- 75 75- 225

50-100

SNRI

SO

30 30 60

100 300-450 Useful for depression,seasonal depression:not recommended for anxiety

disorder treatment because of stimulating effects

Causes less sexual dysfunction (may reverse effects of SSRIsfSNR Is),weight gain,

and sedation

Increased risk of seizures at higher doses

Conliaindicated with history ol sciiurc, stroke,brain tumour,brain injury,dosed

head injury

Important to specify formulation,as available in IR.SR.XI(longest)

Useful for OCD Idomipramine is gold standard),melancholic depression,can also

be used in other types of depression and anxiety disorders

Requires ECG monitoring

Check blood levels if using higher dosage

Highly lethal in overdose

Preferred to tertiary amines because ol lower propensity for anticholinergic

adverse effects

Requires (CG monitoring

Check blood levels if using higher dosage

Highly lethal in overdose

Useful for moderate/seveie depression that does not respond to other

antidepressants:atypical depression;anxiety disorders

Requires strict adherence to MAOI diet,(lova tyramine)

Useful for some anxiety disorders (e.g.social phobia) and depression

Useful In depression with prominent features of insomnia,agitation, or cachexia

Useful in those with constipation as diarrhea is a common side effect

May improve cognitive function

HDRI

TCA (3” Amines) 25-50 150-300

150-300

100-250

amitriptyline (Elavil!

)

imipramine (Tofranil!

)

clomipramine (Anafranil 1 )

25-50

25 50

TCA (2" Amines) nortriptyline (Aventyf ’)

dcsipramine (Norpramin |

25 50 75-150

25 50 150 300

MAOI phenelzine (Nardil -

)

tranylcypromine (Parnate '

)

15 60-90

20 10 - 60

moclobeinidelManerix 300 600 '

l

miltazaplne (Renteronr1)

vilazodone IViibryd )

Serotonin Receptor vortioxeline (Irintellix:

)

Modulator

RIMA 300

HaSSA 15 15 45

SPARI 10 10 40

5 5 20

'for depression (start with X M this dose for treatment ot anxiety disorders)

MAOI = monoamine oxidase inhibitors;NaSSA = noradrenergic and specific serotonergic agent;NDRI = norepinephrine and dopamine reuptake inhibitors;RIMA = reversible inhibition ol MAO-A; SNRI =

serotonin and norepinephrine reuptake inhibitors;SSRI- selective serotoninreuptake inhibitors; TCA *

tricyclic antidepressants;SPARI- serotoninpartial agonist and reuptakc inhibitor

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PS56 Psychiatry Toronto Notes 2023

Treatment Approach for Depression

Select and initiate

a first-line antidepressant Psychopharmacology of SSRIs

Post-Synaptic

Serotonin Receptor

Stimulated

EffectSide Effect Monitor 4

i

’

NO Optimize dose Consider factorsfor

switch vs. adjunct *

Early improvement

after 2-4 wk?

4

5HT1A centrally Relief of depression

Anxiolytic effect Early treatment failure

5HI2A in spinal cord Sena: dysfunction:

delayed ejaculation,

anorgasflia.

decreased interest'

T 1

Switch to another

first-line antidepressant

preferably with

superior efficacy

Switch to a

2nd or 3rd line

antidepressant

Add adjunctive

medication libido YES

5HT205HT2A in brain Activation:anxiety.

insomnia

Worst with fbimetne.

paroiebne

Warn patients anxiety

may worsen *

!first

1-2 wk of treatment

SHT3A in gut Gl upset nausea.

vomiting,bioatng

lake with food

Monitor:consider

longer evaluation

period for more

persistant depression

l r

Continue treatment

for 6-El wk

YES Early improvement

after 2-4wk?

NO

Optimize dose

4

NO

Symptom remission?

YES

Risk factors NO

for recurrence?

Maintain treatment

for 6-9 mo >

YES

Maintain treatment for

2 yr or longer

Figure 3. Depression treatment algorithm

Adapted bom:Sidney H. Kennedy,Raymond W.Lem.Roger S.McIntyre, et al.The Canadian Journal of Pay criatry (61.9). p. 21. copyright : 2020.

Modified by Permission of SAGE Publications.Inc.

•optimization: increase dosage to maximum tolerated or highest therapeutic dosage

•augmentation: the addition of a medication that is not considered an antidepressant to an

antidepressant regimen (i.e. thyroid hormone,lithium, atypical antipsychotics (aripiprazole,

quetiapine, olanzapine, risperidone))

•combination:the addition of another antidepressant to an existing treatment regimen (i.e.the

addition of bupropion or mirtazapine to an SSR1 or SNR1)

•switch:change of the primary antidepressant (within or outside a class)

•note:it isimportant to fully treat depression symptoms (i.e.to remission) to decrease relapse rates

Symptoms of Antidepressant

Discontinuation (mainly from serotonin

reuptake inhibition activity)

FINISH

Flu-like symptoms

Insomnia

Nausea

Imbalance

Sensory disturbances

Hyperarousal (anxiety/agitation)

Serotonin Syndrome

•thought to be due to over-stimulation of the serotonergic system

•can result from medication combinationssuch as more than oneSSRI.SSRl + SNR1.SSRI or SNR!

-

MAOl,SSRI + tryptophan, MAOI + meperidine, MAOI + tryptophan

•rare but potentially life-threatening adverse reaction to SSRIs and SNRIs

•symptoms include: nausea, diarrhea, palpitations, chills, diaphoresis,restlessness, confusion, and

lethargy,but can progress to myoclonus,hyperthermia, rigor,and hypertonicity

•treatment:discontinue medication and administer emergency medical care as needed

•important to distinguish from NMS

Discontinuation Syndrome

•caused by the abrupt cessation ofsome antidepressants; most commonly with paroxetine,

tluvoxamine, and venlafaxine (drugs with shortest half-lives)

•symptoms usually begin within 1-3 d and can include anxiety, insomnia, irritability, mood lability,

N/V,dizziness, headache, dystonia, tremor, chills, fatigue, lethargy,and myalgia ("flu-like symptoms")

•treatment:symptoms may last between 1-3 wk, but can be relieved within 24 h by restarting

antidepressant at the same dosage the patient was taking initially and initiating a slower taper over

several weeks

•consider avoiding drugs with a short half-life

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PS57 Psychiatry TorontoNotes 2023

Table 20. Features of Commonly Used Antidepressant Classes

SSRI SNRI TCA MAOI NDRI RIMA NaSSA SPARI Serotonin

receptor

modulator

Examples fluoxetine.

sertraline.

citalopram

Block serotonin

reuptake only

xenlafaxine.

duloxetine

amitriptyline.

clomipramine

phenelzine bupropion modobemide mirtazapine vilacodone vortioxetine

Mode of

Action

Block

norepinephrine norepinephrine

and serotonin reuptake

reuptake (clomipramine also

blocks serotonin

reuptake)

Block Irreversible

inhibition of MAO

AandB increases

duration that NE.

dopamine,and 5HI

arein the synaptic

cleft by preventing

their degradation

Block

norepinephrine

and dopamine

reuptake

Reversible

inhibitor of

monoamine

oxidase A leads

toincreased

duration of

norepinephrine. o-2 adrenergic

dopamine. receptors

and SHT inthe

synaptic deft by

preventing their

degradation

Enhance central 5HT1A partial

noradrenergic agonism causes

and serotonergic downregulation

activity by

inhibiting

presynaptic

5HT1A agonism

downregulates

presynaptic

5HT1A receptors

to disrnhibit

serotonin

release,and

5HT7 antagonism

theoretically

enhances cognitive

function

ofpresynaptic

5HT1Areceptors

todisinhibit

serotonin

release,and 5HT4

agonism treats

constipation

Side Effects CMS: CHS:dizziness. CHS (usually

headache,

tremor,insomnia, headache.

CNS:sedation. CNS:sedation

Gl:nausea,

diarrhea

Anticholinergic Gl:nausea

effects:(see Table

Antihistamine

effects (minimal):

sedation,weight

Low dose

restlessness. side effects

tremor,insomnia, similar toSSRIs 77.KJ3)

(serotonergic) Noradrenergic

effects:tremors,

tachycardia,

sweating

a-t adrenergic

effects: orthostatic

hypotension,falls

ORS prolongation

minor):dizziness, dizziness

Endocrine:

tremor,insomnia increase in

cholesterol,

increase in

hypotension triglycerides,

dysrhythmia.HIM Gl:dry mouth. weight gain

Gl:dry mouth. N/V.diarrhea, Gl:constipation.

N/Y.constipation, abdominal pain. AIT elevation

dyspepsia

GU: delayed

ejaculation

Other:

diaphoresis

gain agitation,

anxiety,lower CVS:

seizure threshold dysrhythmia.

headache,

drowsiness.EPS Higher dose

Gl:NY.diarrhea, side effects:

CVS:orthostatic

hypotension,

hypertensive crises

with lyramine

rich foods (e.g.

wine,cheese),

or combination

with serotonergic

or adrenergic

medications,

headache,flushes,

reflex tachycardia,

postural

hypotension,

insomnia

Minimal

anticholinergic

effects

abdominal tremors.

tachycardia.

sweating.

insomnia.

orthostatic

hypotension.

increase in BP

(noradrenergic)

SIADH

cramps,

weight gam

Sexual

dysfunction:

erectile

dysfunction,

anorgasmia

CVS:increased

HR.increased

OTc.serotomn

syndrome.

SIADH.decreased

platelet

aggregation -

increased risk of

bleeding

Relatively safein Tachycardia Toxic in overdose

and H' V seen in 3 times therapeutic

acute overdose dose may be lethal

Presentation:

anticholinergic

effects. CNS

stimulation,then

depression and

seizures

ECG:prolonged ORS

and OIc (relied

severity)

Treatment:

activated charcoal,

cathartics,

supportive

treatment,

IV diazepam

for seizure,

physosligmine

salicylate for coma

Do not give ipecac,

as can cause

rapid neurologic

deteriorationand

seizures

decreased

appetite

Risk in

Overdose overdose

Risk of fatal

overdose when overdose

combined with

SSRIs.SNRIs.or

clomipramine

Relatively safe in Relatively safe in Relatively safe in

overdose

Toxic in overdose,

but wider margin of

safety than TCA

Tremors and

seizures seen in

overdose

overdose

MAOI.SNRI

Interactions SomeSSRIs

(fluoxetine,

fluvoiamine.

paroxetine)

strongly inhibit

cytochrome

P450 enzymes,

therefore

win affect

levels of drugs

metabolized by

P450 system

MAOI.SSRI MAOI.SSRI

Low inhibition ElOH

of cytochrome

P450

compounds

Hypertensive crises MAOI

with noradrenergic Drugs thatreduce Opioids

medications|i£. seizure threshold:

TCA.decongestants, anbpsychotics.

amphetamines) systemic

Serotonin syndrome steroids,

with serotonergic guinolone

drugs (i.e.SSRI. antibiotics.

SNRI.tryptophan. antimalanal

dextromethorphan) drugs

Drug MAOI.paroxetine MAOI.RIMA MAOI MAOI

No inhibition of

cytochrome P450

r T

L.J

+

PS58 Psychiatry TorontoNotes 2023

Mood Stabilizers

General Prescribing Information

• examples: lithium,divalproex, lamotrigine, carbamazepine

• used mainly for long-term stabilization of bipolar disorder, also used asfirst-line monotherapy or in

conjunction with atypical antipsychoticsfor acute episodes of bipolar disorder (i.e.depression and

mania)

• vary in their ability to “treat” (i.e.reduce symptoms acutely) or “stabilize” (i.e.prevent relapse and

recurrence) manic and depressive symptoms; multi-agent therapy can be avoided in many patients but

it is common

• before initiating, get baseline: CBC with differential and platelets, ECG (if patient >45 y/o or

cardiovascular risk),BUN, creatinine,extended electrolytes, TSH, LFTsfor divalproex and

carbamazepine

• screening for:pregnancy, thyroid disease, neurological,renal, liver, cardiovascular diseases

• full effects may take 2-4 wk, thus may need acute coverage with benzodiazepines or antipsychotics

Specific Prescribing Information

• detailed pharmacological guidelines available online from the Canadian Network for Mood and

Anxiety Treatments(CANMAT) and International Society for Bipolar Disorders (1SBD)

• for clinical information for treating bipolar disorder (see Mood Disorders, PS10)

• be mindful that divalproex and carbamazepine are teratogenic thus if prescribed for women at

reproductive age, a reliable contraceptive strategy is required

Table 21. Commonly Used Mood Stabilizers

Lithium Lamotrigine (Lamictal ) Divalproex (Epival } Carbamazepine (Tegretol )

Indications 1st line

Acute mania (monotherapy or with

adjunct SGA)

Bipolar Idepression (combination with

lithium or SSRI)

Bipolar disorder maintenance

(monotherapy or with ad.unct SGA)

2nd line

Acute mania (monotherapy)

Bipolar disorder maintenance

(monotherapy or in combination with

lithium)

1st line

Acute mania (monotherapy or with

adjunct SGA)

BipolarIdepression (monotherapy or in

combination with divalproei,SSRI,or

bupropion)

Bipolar disorder maintenance

(monotherapy or with adiunct SGA)

1st line

BipolarIdepression (monotherapy)

Bipolar disorder maintenance (limited

efficacy inpreventing mania,more

effective when combined with titnum)

Other uses

Bipolar II depression

Other uses

Rapid cycling bipolar disorder

Other uses

Bipolar II depression

Rapid cycling bipolar disorder

Mixed phase/dysphoricmania

Other uses Hot recommended for acute mania

Bipolar It depression

Augmentation of antidepressants in MOD

and OCD

Schizoaffective disorder

Chronic aggression,antisocial behaviour

Recurrent depression

Unknown

Therapeutic response within 7-14 d

Adult 600-1500 mg/d

Geriatric:150-600 mgd

Usually daily dosing

Blood levels monitored and dose adjusted

accordingly

Adult:0.8-1.0 mmol/ (1.0-1.25 mmol/L

for acute mania)

Geriatric:0.6-0.8 rmtol:

Mode of Action May rahibrt5-HT3 receptors

May potentiate DA activity

Hote:very slow titrationrequireddue

to riskof Stevens-Johnson Syndrome

Oose adjusted inpatients taking other

anticonvulsants such as divalproei

Daily dose:100-200 ing/d

Therapeutic plasma level not

established

Dosing based on therapeutic response

Depresses synaptic transmission

Raises seizure threshold

750-2500 mg/d

Usually daily dosing withER preparation

Depresses synaptic transmission

Rases seizure threshold

400-1600 mgi'd

Usually BID orTID dosing

Dosage

Therapeutic Level 17-50 mmol/L

Same therapeutic levels as used for

seizure prophylaxis

(no data specific for mood stabilizing

effect)

Monitor serum levelsevery 5-7 d until

therapeutic

LFTs weekly x 1mo.thenmonthly,then

q2-3 mo due to risk of l.ver dysfunction

Watch for signs of liver dysfunction:

nausea,edema,malaise

Check platelets andmonitor levels to

adjust dosage andconfirm adherence

Skin:rash(consider discontinuing due to Gl:liver dysfunction. H V.diarrhea

risk of Steven-Johnson syndrome which CHS:ataxia,drowsiness,tremor,

is an emergency),slow dose titration to sedation,cognitive blurring

reduce risk

Otherwise,usually well tolerated

(Gl:H/V.diarrhea

CHS:ataxia,dizziness,diplopia,

headache,somnolence

Other:anxiety)

350-700pmol/L

Same therapeutic levels as used for

seizure prophylaxis

(no data specific for mood stabilizing

effect)

Monitor serum levels every 5-7 duntil

therapeutic

Weekly blood counts for 1st mo.due to

risk of agranulocytosis

Watch for signs of blood dyscrasas:

fever,rash,sore throat,easy bruising

Monitoring Monitor serum levelsevery S-7 d until

therapeutic (always12h after dose)

Then monitor monthly,then q2-3 mo

Monitor thyroid function.creatinine

q6 mo

Monitor for skin rash and suicidality

when initiating treatment

SideEffects Gl:H/V,diarrhea,stomach pain

GU:polyuria,polydipsia,nephrogenic

diabetic insipidus,glomerulonephritis,

renal failure,decreased glomerular

filtrationrate

CHS:fine tremor,headache,fatigue,

lethargy

Hematologic:reversible benign

leukocytosis

Other:teratogenic (Ebstein's anomaly),

hypothyroidism,weight gain,edema,

worsening of psoriasis,bradycardia.ECG

changes

HSAIDs,thiazides.ACEI.and

metronidazole decrease clearance,risk

for lithium toxicity

Gl:H/V.diarrhea, hepatic toxicity

CHS:atana.dizziness,slurred speech,

drowsiness,confusion,nystagmus,

diplopia

Hematologic:transient leukopenia

(10%).rareagranulocytosis,aplastic

anemia

Stun:rash (5% risk;consider

discontinuing drug because of risk of

Stevens-Johnson syndrome)

Other:neural tube defects when used

inpregnancy

Other:hair loss,weight gain,

thrombocytopenia,nexal tube defects

when used in pregnancy,polycystic

ovarian syndrome r m

t

- J

+

Interactions 0CP 0CP

PS59 Psychiatry Toronto Notes 2023

Lithium Toxicity

• clinical diagnosis as toxicity can occur at therapeutic levels

• common causes:overdose,sodium/fluid loss, concurrent medical illness or initiation of NSAIDs,

diuretics, or ACE1

• clinical features

Gl:severe nausea/vomiting and diarrhea

cerebellar: ataxia,slurred speech,lack of coordination

cerebral: drowsiness, myoclonus, tremor, upper motor neuron signs,seizures, delirium, coma

• management

discontinue lithium for several days and begin again at a lower dose when lithium level hasfallen

to a non-toxic range

monitor serum lithium levels, creatinine, BUN, electrolytes

IV saline

hemodialysis if lithium >2 mmol/L, coma,shock,severe dehydration,failure to respond to

treatment after 24 h, or deterioration

Longterm lithium use can lead to a

nephropathy and diabetesinsipidusin

some patients

Anxiolytics

•anxiolytics mask or alleviate symptoms

•indications

• short-term treatment of anxiety disorders, insomnia,alcohol withdrawal (especially delirium

tremens), barbiturate withdrawal, akathisia due to antipsychotics,seizure disorders,

musculoskeletal disorders,agitation or aggression associated with acute mania,or psychosis

•relative contraindications

major depression (except as an adjunct to other treatment), history'of drug/alcohol misuse,

caution in pregnancy/breastfeeding

myasthenia gravis is a relative contraindication for benzodiazepines

•mechanism of action

benzodiazepines:potentiate binding of GABA to its receptors;results in decreased neuronal

activity

buspirone:partial agonist of 5-HT1A receptors

Benzodiazepines

•should be used for limited periods(i.e.davs-weeks) to avoid tolerance and dependence

•all benzodiazepines are sedating, decrease respirator)'drive, and increase risk for falls, confusion,

and motor vehicle accidents;be wary with use in the elderly,especially in combination with other

psychotropic medications

•have similar efficacy,so choice depends on half-life,metabolites, and route orschedule of

administration

•taper slowly over weeks-months because they can cause withdrawal reactions(see below)

•beware of use with alcohol and other CNS depressants because of potentiation of CNS depression;

caution with drinking and driving/machinery use

•side effects

CNS: drowsiness, cognitive impairment, reduced motor coordination (falls), memory impairment

dependence, tolerance, withdrawal

•withdrawal

low dose withdrawal symptoms:tachycardia, HTN, panic, rebound insomnia,anxiety,impaired

memory and concentration, perceptual disturbances

• high dose or rapid withdrawal symptoms: hyperpyrexia,seizures, death

onset: 1-2 d (short-acting), 2-4 d (long-acting)

duration:days-weeks

• complication with above 50 mg diazepam/d or abrupt withdrawal:autonomic hyperactivity,

seizures, delirium, arrhythmias

management: taper slowly; may need to switch to a long-acting benzodiazepine

similar to but lesssevere than alcohol withdrawal; can be fatal

•overdose

overdose is common but rarely fatal unless combined with othersubstances

more dangerous or potentially fatal when combined with alcohol,other CNS depressants,opioids,

orTCAs

Benzodiazepine AntagonistFlumazenil (Anexate:

)

Use for suspected benzodiazepine

overdose

Specific antagonist at the

benzodiazepine receptorsite

Benzodiazepines That areSafe for

Patients with Impaired Liver Function

LOT

Lorazepam

Oxazepam

Temazepam

Buspirone (Buspar-

)

•primary use:GAL)

•may be preferred over benzodiazepines because it is non-sedating, has no interaction with alcohol,

does not alterseizure threshold, not prone to abuse

•onset of action:2 wk

•side effects:dizziness, drowsiness, nausea, headache, nervousness, EPS

Z-drugs for Sleep

•non-benzodiazepine sedatives indicated for short-term management of insomnia

•examples include zopiclone (Imovane*), eszopidone (Lunesta*), and zolpidem (Sublinox’) +

•anecdotally provide a more restful sleep than benzodiazepines

•similar side effect profile and warnings to benzodiazepines

•should not be used long-term due to side effects and likelihood of dependency

PS60 Psychiatry Toronto Notes 2023

Table 22. Dosing and Indications for Common Anxiolytics

Class Drug Dose Range ti/2|h) Appropriate Use

(mg/d)

tmax (h)

Benzodiazepines

Long-acting Clonazepam|Rivotril!

) 0.25- 4 18-50 Seizure prevention,akathisia.generalized anxiety disorder, panic

disorder

Seizure prevention, muscle relaxant, alcohol withdrawal,

generalized anxiety

Alcohol withdrawal

Should be avoided

Should be avoided due to high dependency rate

Alcohol withdrawal (no first- passliver metabolism), akathisia.

short-term sedation (or anxiety during procedures (e.g.Cl or MRI).

generalized anxiety;sublingual or IM for rapid action

Alcohol withdrawal (no first- pass liver metabolism),generalized

anxiety disorder

Should be avoided

Shortest tV2,rapid sleep without daytime sedation (e g.overnight

plane travel), but risk of rebound insomnia

1- 4

Diazepam (Valium1

-) 2 40 30-100 1-2

Chlordiazepoxrde (Librium ;

)

Flurazepam|Dalmane:

)

Alprazolam (Xanax 1 )

Lorazepam (Ativan -)

5-300 30-100 1-4

15-30 50-160 0.5-1

Short-acting 0.25-4.0 6-20 1-2

0.5-6.0 10 -20 1-4

Oxazepam (Serax '

) 10 -120 8-12 2- 3

temazepam (Restoril 1

)

triazolam IHs!cion ’

)

7.5 -30 8-20 2-5

0.125-0.5 1.5-5 1-2

Azapirones

Buspirone (Buspar - ) 15- 30 2-3 1-1.5 Generalized anxiety disorder

Somatic Therapies

Electroconvulsive Therapy

• the fastest and most effective acute treatment of depression

• ECT is a safe and controlled way of producing seizures to treat mental illness

• various methodological improvements have been made since the first treatment in 1938 to reduce

adverse effects

• modern ECT:induction of a generalized seizure using an electrical pulse through scalp electrodes

while the patient is under general anesthesia with a muscle relaxant

• considerations: unilateral vs. bilateral electrode placement, pulse rate, energy, number, and spacing of

treatments

• usual course is 6-12 treatments, 2-3 treatments per wk

• indications

treatment-resistant depression (unipolar, bipolar I, bipolar II): psychotic features, catatonic

features, when medications may be unsafe or rapid response is needed (e.g. cachexia,severe

dehydration, frail elderly, high suicide risk, pregnancy)

• catatonia:refractory,severe, or life-threatening

schizophrenia: treatment-resistant, acute symptoms, catatonia, history of NMS

mania:refractory,severe or life-threatening situation

• personal or family history of good response to ECT

inconclusive evidence for OCD

• adverse effects: risk of anesthesia (equal to risk of ECT), memory loss (may he retrograde and/or

anterograde, tends to resolve by 6-9 mo, permanent impairment controversial), transient headaches,

transient myalgias

• unilateral ECT causesless memory loss than bilateral but may not be as effective

• contraindications: no absolute contraindications; relative contraindications: increased intracranial

pressure,recent (<4 wk ) hemorrhagic stroke, recent (<2 wk) Ml, requiresspecial monitoring

ECT in Society

Prior to the 1940 s. ECT was performed

without the use of muscle relaxants.

resulting in seizures with full scale

convulsions and rare but serious

complications such as vertebral and

long-bone fractures.This practice may

have led to negative societal perceptions

of ECT ,further perpetuated by negative

depictions in popular culture.Despite

ongoing stigmatization. ECT as it is

practiced today is an effective and safe

option for patients with severe mental

illness, including depression

Electroconvulsive Therapy for treatment

Resistant Schizophrenia

C ochrane OB Syst Rev 2019:CD 0I1847

Purpose:Assess henehtsand harmsof EC T for people

with treatment-resistant schizophrenia.

Outcomes: Moderate-quality ev dence indicatesthat

relative to standard care.ECT has a positive effect

on medium-term clinical response for peoplewith

treatment-resistantschizophrenia. However,there is

no clear and convincing advantage nr disadvantage

lor adding ECI to standard care lor other ouhomes.

Repetitive Transcranial Magnetic Stimulation (rTMS)

• noninvasive production of focal electrical currents in select brain circuits using magnetic induction

• indications:strong evidence for treatment-resistant depression and pain disorders; possibly efficacious

for anxiety disorders, PTSD, eating disorders, and substance use disorders

• adverse effects: common -transient local discomfort, hearing issues, or cognitive changes; rare -

seizure,syncope, mania induction

Magnetic Seizure Therapy (Experimental) r T

• magnetic seizure therapy ( MS I ) is generalized seizure induction using strong magnetic current

• early studies demonstrate efficacy for depression as well as anxiety, with reduced memory effects vs.

ECI

+

PS61 Psychiatry Toronto Notes 2023

Neurosurgical Treatments

Ablative/Lesion Procedures

• used for MDD or OCD unresponsive to all other forms of treatment;efficacy ranges from 25-75%

depending on procedure

• adverse effects:related to lesion location and size, high-risk ofsuicide in those who are not helped by

surgery

• focused ultrasound therapy (PUS) is an experimentalsurgical technique under investigation for the

treatment of MDD,OCD with the advantage of avoiding an open skullsurgery

Deep Brain Stimulation (Experimental)

• placement of small electrode leads in specific brain areas to alter neuronal signaling

• most evidence for treating OCD,some evidence for other disorderssuch as treatment-resistant MDD

• response rates(>50% symptom reduction) of 40-70%,adverse effects related to surgical risks and poor

treatment response

Vagus Nerve Stimulation

• direct,intermittent electricalstimulation of left cervical vagus nerve via implanted pulse generator

• used for chronic,recurrent MDD with poor response to previous therapy'and KCT

• slow onset,approximately 30% response rate at 1 yr

Other Therapy Modalities

Phototherapy (Light Box Therapy)

• bright light source exposure (usually 10000 lux) for 30 min daily within the first hour of awakening

• proposed mechanisms: reverses pathological alterations in circadian rhythm through action on

suprachiasmatic nucleus

• indications:seasonal affective disorder (SAD), non-seasonal depression (as augmentation), and some

sleep disorders

• adverse effects:mania induction, reaction with photosensitizing drugor photosensitive eye orskin

conditions

Aerobic Exercise

• moderate-intense aerobic exercise is associated with acute increased release of serotonin,

phenethylamine,brain-derived neurotrophic factor,endogenous opioids,and cannabinoids(likely

this combination is what contributes to the “runners high”)

• associated with long term increases in grey matter in multiple areas,as well asimprovementsin

cognition,memory, and stresstolerance

• indications:monotherapy for mild-moderate MDD;adjunctive therapy for moderate-severe MDD

• may be helpful in PTSD,schizophrenia

r ~t

LJ

+