Flashcards: 2. psychotherapeutic agents

pain relief, seizures, anaesthesia

stimulant/depressant, euphoria, hallucinations

effects on individual neurons (excitation/depression) does not equal overt functional effects

ex: alcohol is a depressant but produces overt stimulant effect -> depresses activity in frontal lobe that is responsible for impulse control

free lipid soluble > ionize/protein bound drugs (for crossing BBB)

underdeveloped in infants -> vulnerable to CNS drugs

Protects against toxic substances

Impairs therapeutic Tx

limited CNS pathophysiology understanding = uncertainty of CNS agents action

multiple CNS transmitters with unclear precise roles

almost always alters synaptic neurotransmission

brain is always changing

1. decreased drug effects over time: decreases therapeutic effects (=tolerance) and decreases adverse effects (=habituation)

2. behaviour changes and addiction: withdrawal Sx (physical dependence), cravings (psychological dependence), highjacking of motivation + reward pathways (most drugs of abuse are CNS drugs)

3. delayed onset efficacy: increases drug effects over time, beneficial response from CNS adaptation rather than direct synaptic transmission alterations

drugs of choice for schizophrenia

1st generation (FGA) and 2nd generation (SGA)

FGA has higher EPS than SGA

extrapyramidal symptoms

early reactions = acute dystonia, Parkinsonism, akathisia

late reactions = tardive dyskinesia

dopamine (D2) antagonists -> block dopamine receptors

reduced dopamine synthesis and release = antipsychotic effect

remember SCZ hypothesis = too much dopamine

but remember decrease in dopamine = Parkinson, motor impairments

EPS

sedation -> histamine receptors

orthostatic hypotension -> NE

anticholinergic effects -> acetylcholine

QT prolongation + cardiac effects

potency : low

EPS: moderate

sedation: high

orthostatic hypotension: high

anticholinergic effects: moderate

potency : high

EPS: very high

sedation: low

orthostatic hypotension: low

anticholinergic effects: low

believed to have superior efficacy

lower EPS

higher metabolic effects (diabetes, dyslipidemia)

cost 10-20x more

act on mesolimbic pathway (this is unregulated in schizo)

dopamine (D2) and serotonin (5HT2A) antagonists

also block histamine, NE and Ach receptors

abort and prevent acute psychosis: onset 1-2 days, peak effects 2-4 weeks

select agent based on toxicity profile to maximize adherence

EPS

sedation

orthostatic hypotension

anticholinergic effects

metabolic effects

significant QT prolongation

prolactin elevation

EPS: very low

sedation: high

orthostatic hypotension: moderate

anticholinergic effects: high

metabolic effects: high

significant QT prolongation: yes

prolactin elevation: low

metabolized by CYP3A4

EPS: moderate

sedation: low

orthostatic hypotension: low

anticholinergic effects: none

metabolic effects: moderate

significant QT prolongation: yes

prolactin elevation: high

NOT metabolized by CYP3A4

EPS: low

sedation: moderate

orthostatic hypotension: moderate

anticholinergic effects: moderate

metabolic effects: high

significant QT prolongation: no

prolactin elevation: low

NOT metabolized by CYP3A4

most effective at improving Sx

weak D2 antagonist = decreased EPS

excellent for pt with severe EPS

fatal agranulocytosis

onset 6 months, mechanism unknown

monitor WBC weekly !!!

neuroleptic malignant syndrome: fatal syndrome more likely w/high potency FGA

Sx: rigidity, fever, autonomic dysfunctions

dantrolene (muscle relaxant) + bromocriptine (DA agonist)

dry mouth, consitpation, urinary retention

via blockage or alpha1-adrenergic receptors -> no compensatory vasoconstriction

monitor BP and pulse

via blockade of histamine H1 receptors -> decreases over time

via DA inhibition -> DA cannot inhibit prolactin release

manifestations: menstrual irregularities/ breast growth/ galactorrhea

problematic in pt w/seizures disorders

adjust anti-seizure meds dosage up if necessary

decreased libido + erectile dysfunction -> decreased pt adherence

low potency FGA > high potency FGA

very rare -> monitor WBC count if sign of infection

most likely with chlorpromazine + clozapine

chlorpromazine + haloperidol prolong QT interval

ECG + potassium determination before + after Tx

off label use -> double mortality risk -> avoid at all costs

risk of EPS to baby if exposed during 3rd trimester

not recommended to discontinue TX -> monitor instead

addiction and abuse are unlikely

mild withdrawal Sx if abruptly stopped -> taper off gradually

anticholinergic drugs -> increased anticholinergic effects

alcohol + CNS depressants -> additive effects

L-dopa -> antagonistic effects and vice versa

acute episode suppression

prevention

improve QoL

individualized based on efficacy/toxicity/cost

history of diabetes -> avoid Rx w/metabolic effects

resistant to initial Tx -> clozapine, olanzapine

no contraindications -> cheaper Rx

bedtime dosing decreases daytime drowsiness/sedation

higher dose for acute psychosis vs lowest effective dose for maintenance

acute therapy: PO (liquid therapy has to be diluted)

prevention: IM depot -> increased adherence and decreased toxicity

Sx decrease in 1-2 days

1-2 wks for significant improvement

full effect over few months

treat at least for 12 moths post acute episode -> poor adherence

if Sx-free: taper off gradually for less withdrawal

favour IM depot (long acting)

1. Cognitive behaviour therapy: forming therapeutic alliance + support system

2. pt + family education: strict schedule + adherence; low risk of addiction

3. vocational training: provide feelings of agency, productivity + independence

benzodiazepines: decreased anxiety + stabilize sleep

antidepressants for depressive Sx

clear benefits only for severe depression, unclear for mild/moderate

adaptive neuronal changes > enhanced neuronal transmission = the efficacy of drug

delayed therapeutic response:

initial effects around 1-3 weeks

full effects around 12 weeks

try for at least 1 month

do not administer PRN -> might halt or create abnormal neural changes

new: SSRIs -> safer !!!

old: TCAs, MAOIs

angomelatine

amitriptyline

mirtazapine

escitalopram

paroxetine

vortioxetine

venlafaxine

agomelatine

citalopram

escitalopram

fluoxetine (only efficient option for minors)

sertaline

vortioxetine

start low dose + increase gradually:

- if inefficient after 4-8 wks, switch Rx

- Tx for 4-9 months minimum

- taper off gradually over several wks

suicide, mostly to pt under 25 years

if suicide risk is high, hospitalization is best option!

suicide risk of untreated depression > antidepressant suicide risk

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 checking (putting meds in cheek)

suicide hotline

any form of depression around the time of delivery

more than 2 weeks

moderate to sever dysfunction

favour initial therapy with SSRIs

reuptake inhibitors: selective serotonin and serotonin + NE

tricyclic (TCA)

monoamine oxidase inhibitors (MAOI)

atypical

selective serotonin reuptake inhibitor: prevents reuptake of serotonin, so continues to float in synaptic cleft, will activate receptors on other neuron, increase activity on neuron

most commonly prescribed antidepressants

serotonin + NE reuptake inhibitors

- block reuptake of serotonin AND NE

- similar efficacy + adverse effects as SSRIs

- but inferior tolerability

serotonin syndrome:

risk of death

onset 2-72h post start

altered mental states, sweating, fever, tremors

DISCONTINUE Rx ASAP

persistant pulmonary hypertension:

risk of death or cognitive impairment

ventilatory support + close monitoring

neonatal abstinence syndrome:

respiratory distress + seizures

monitor closely for min 48 hrs

sexual dysfunction: affects 70%

manage: patient education, drug holidays, dose decrease

weight gain: due to decreased sensitivity of appetite regulating 5-HT receptors

withdrawal Sx: taper off gradually

other antidepressants:

MAOIs: together increase serotonin levels + risk of serotonin syndrome

TCAs: SSRIs increase concentration

antipsychotics:

lithium: SSRIs increase concentration

others:

anti platelet + anticoagulation: increase bleeding risk

major depression - 2nd line Rx

neuropathic pain

fibromyalgia

ex: amitriptyline

blocks serotonin re-uptake transporter

blocks noradrenaline re-uptake transporter

blocks histamine receptors transporter

orthostatic hypotension -> adrenergic

sedation -> histamine

anticholinergic, cardiac toxicity -> acetylcholine

MAOIs cause severe hypertension

sympathomimetic + anticholinergic Rx

other sedatives (ex: alcohol, opioids)

overdose risk (TI around 8)

major depression - 2/3rd line Rx

atypical depression - 1st choice Rx

monoamine oxidase A inactivates NE and 5-HT (instead of blocking reuptake, blocking breakdown) -> anti depressive effect

monoamine oxidase B inactivates DA -> antiparkison effect

orthostatic hypotension -> more NE in CNS reduces sympathetic firing

other antidepressants (SSRIs, TCAs)

antihypertensive drugs

many others...avoid all Rx unless also prescribed

foods + drinks high in tyramine -> can cause hypertensive crisis

tyramine is precursor of NE, MAO is responsible to metabolize, but MAOI blocks MAO, so tyramine never gets metabolized

chemistry similar to TCAs but effect like SSRI but faster onset

blocks presynaptic alpha2-receptors (increases 5-HT + NE release)

generally well tolerated

ADR: sedation + weight gain due to histamine block

interactions: CNS depressants + MAOIs increase sedation

action: melatonin agonist + 5-HT antagonist

- melatonin action normalizes sleep cycle

- 5-HT antagonism increases DA + NE release in frontal lobe

- called 'DA_NE distributor'

toxicity: well tolerated, potentially less toxic

ADRs:

- possible hepatoxicity (monitor ALT and AST)

- sleep disturbances + nightmares

S-adenosylmethionine (SAMe): superior to TCA and improved Sx in SSRI-resistant pt

MoA: increased synthesis of NE, 5-HT, DA in CNS

St-John's wort: superior to placebo for mild moderate depression

unclear action, p450 + P-glycoprotein inducer

BUT limited efficacy or insufficient evidence

produces generalized seizure for 20-30s to reset brain

requires 6-12 treatments

short acting muscle relaxant + IV anesthetic for safety

consciousness unnecessary for benefits

ADRs: transient amnesia, cognitive impairment

relatively safe + fast benefits: 8% relapse with ECT vs 73% without

good for severe depression unresponsive to Rx

transcranial magnetic stimulation

vagus stimulation: developed as anti-seizure but less Sx of depression, super $$$$

light therapy: increases 5-HT transmission, response proportional to light intensity, low cost

healthy lifestyle

exercise is more efficient than drugs for depressive Sx

medication reduces activity of DMN

best therapy = psychotherapy + pharmacotherapy

1st line drug option = SSRIs

significant SBN potential: health life, social support, education, foster collaborative relationship

SSRIs and buspirone -> delayed effects

- best for cognitive + psychic Sx

- low abuse potential

- no interactions with CNS depressants

benzodiazepines -> rapid relief

- best for somatic Sx alleviation

- abuse potential explains declined use

- gradual tapering off = crucial to avoid withdrawal

1st line: SSRIs

- decrease anticipatory anxiety, avoidance behaviours, frequency + intensity of attacks

- transient rebound anxiety upon initiation -> start w/low dose

2nd line: TCA/MAOI/benzodiazepine

- efficient but less well tolerated vs SSRI

Non drug:

- CBT + MBSR

- avoid stimulants

healthy lifestyle

1st line: SSRIs

- benefits via increased 5-HT transmission

- delayed onset

- continue for at least 1 year

non drug Tx:

- fear control exercises -> very efficient

- deep brain stimulation for severe cases

1st line: SSRIs

- delayed onset around 4 weeks

-very useful for pt obliged to face frequent anxiety situations

2nd line: benzodiazepines + B-blockers

- rapid onset

- useful for performance anxiety

Non drug:

- gradual social exposure exercises

remember 3 core Sx: re-experiencing event, avoiding reminders, hyperarousal

1st-line: SSRIs

2nd line: mirtazapine, TCA or MAOI

no evidence for: buspirone, buproprion, benzodiazepines

new evidence: MDMA + psychedelics

non drug:

- trauma focused exposure therapy

- stress inoculation training

mood stabilizers: lithium, valproate, carbamazepine

- 1st line: abort manic episodes, prevent recurrence

antipsychotics: SGA>FGA

- adjunct to mood stabilizers for severe mania

antidepressants: SSRIs, bupropion

- adjunct to mood stabilizers for severe depressive

used to abort + prevent manic episodes

MoA unknown

very short T1/2 + very narrow TI

administer PO in divided daily doses

kidney excretion: watch for renal impairment + sodium levels

NEED TO MONITOR PLASMA LEVELS -> keep below 1.5, this is superrrrrrr important, can die

CNS

- teratogen: avoid during 1st

- tremors: mitigate w/B-blockers

GI

- Disturbances: common but transient

Renal

- toxicity: mostly w/chronic lithium therapy

- antagonism of ADH, must drink frequently

Interactions

- diuretics: increase Na+ loss leads to lithium accumulation

- NSAIDs: increase lithium renal reabsorption (except aspirin)

anti epileptic drug w/mood stabilizing effect

compared to lithium

- better onset + safety

- more effective vs manic Sx

- less effective vs suicidal ideation

- less effective vs depressive Sx

- higher rate of relapse

ADR: hepatoxicity, teratogen

anti epileptic drug w/mood stabilizing effect

slightly inferior alternative to valproate

ADR:

mild neurologic effects (common)

severe hematologic effects (rare)

many interactions w/P450 enzymes