Antipsychotics, Mood Stabilizers, adn Stimulants

glutamate

excitatory

GABA

• dominant inhibitory NT

ACh

• acts on nicotinic adn muscarinic anticholinergic receptors

• actions to motivation, sleep wakefullness, and memory, as well as attention adn learning

biogentic amines

acgions related to arousal, mood, synaptic plasticity

• dopamine (DA)

• norepi (NE)

• seritonin (SE)

• histamine

what does NE act on

• acts on alpha and beta adrenergic receptors

what does DA act on

• acts on D1- type group (D1 and D5) adn D2 type group (D2, D3, D4) receptors

what does SE act on

• acts on 7 sub groupd

  • 5HT1 to 5HT7 receptors

what NT modulate the excitability of neurons which drives the magnitude of response to fast acting transmitters such as GLu and GABA

• ACH

• DA

• NE

• SE

dopamine (DE)

• part of reward system

• reinforcement of behavior when doing somethig enjoyable

• motivation, pleasure

• learning, attention, cognition

• mvmt (motor control)

Norepi (NE)

• arousal- wakefullness, alertness, sensory signal detection

• cognition- working memory, attention, task engaement

• rxns to stress

serotonin/SE/5HT

• emotional processing, mood, memory

• regulating sleep wake cycles, appetite, adn energy

• involved oni blood clotting

• regulates gastric emptying, gut motility

• libido/sexual function

first generation antipsychotics- FGAs (typical)

• pure D2 antagonism

• haloperidol- high potency

• chlorpromazine- low potency

• fluphenazine- high potency

• perphenazine

second generation atipsychotics -SGAs (atypical)

• D2 + 5HT2A antagonism, (± D2 partial antagonism)

• clozapine

• questiapine

• olanzapine

• risperidone

• ziprasidone

• lurasidone

atypicals/third generation antipsychotics

• ariPRPrazole

• brexPIPrazole

• caRIPrazine

• lumateperonone

antiepileptic drugs (anticonvulsants)

• valproic acid

• carbamazepine

• lamotrigine

stimulants - amphetamine based stimulant

• dextroamphetamine

• mixed amphetamine salts

• lisdexamfetamine (prodrug)

stimulants- methylphenidate based stimulant

• methylphenidate

• dexmethylphenidate

• serdexmethylohenidate

• serdexmethylphenidate ad dexmethylpheidate (70% prodrug, 30% IR)

non stimulants for ADHD- NE reuptake inhib

• atomoxetine

• viloxazine XR

non stimulant for ADHD- other agents

• guanfacine’clonidine

• cupropion XL

anticholinergic

benztropine

VMAT2 inhib

• valbenazine

• deutetrabenazine

atypical antiphycotics effects

• modulate dopamine signaling, stabilizes dopainergic systems

• provide partial stimulation at D2 when natural DA levels are low, blocks excess DA signaling when DA levels are high

  • act as partial agonists

positive effects of schizophrenia

• hallucination

• delusions

• disorganized speech

• disorganized/catatonic behvaior

negative sx of schizophrenia

• flat affect

• alogia

• anhedonia

• avolition

cognitive sx schizophrenia

• impaires attetion

• working memory deficits

• executive dysfinction

• poor insight/judgement

what type of med if most reliabel for positive sx of schizophrenia

• anntipsychotics

__has higher affinity for D2 receptor

first generation antipsychotics

mesolimbic dopamine pathway

• reward, pleasure, euphoria

• effect: improves positive

mesocortical dopamine pathways

• cognition, executive fct, emonigrostriatal dopamine effection, affect

• effect: may worsen neg/cognitive

nigrostriatal dopamien pathway

• purposeful mvmt

• effect: ADR: EPS

tuberoinfundibular dopamine pathway

• DA inhib prolacton release

• effect: ADR: Hhypperprolactinemia

dopamine receptos

• all antipsychotics have some degree of D2 antagonism

• blocking D2 in meolimbic dopamine circuit produces antipsychotic effect

• blockign D2 i nigrostriatal system produces EPS SE

serotonin receptors

• SGAs only

• blockade conributes to weight gain adn sexual side effects

HAM

• histamine- bloackafe of H1 receptors contributes to sedation, anti-emetic effects adn weigh tgain

• alpha adrenergic receptors- effects receptors- blockade of alpha1 and alpha 2 contributes to orthostatic hypotension, hypersalivation, ad incontinence effects

• muscarinic receptors- blockade of M1 and M2 can cause dry mouth, blurred vision, constipation, urinary retention, sinus tach, sedation

antipsychotics influence dopamie signaling in which pathways

across all four pathways no matter what

high potency FGA

• more EPS

• haloperidol

• fluphenazine

low potency FGA

• more sedation/anticholinergic

• chlorpromazine

FGA tradeoff

• mvmt/prolactin problems

SGA tradeoff

• metabolic problems

routes of admin

• oral/ODT- preferred for most

• short acting IM (agitation)

• long actng injectable depot (LAI)

  • improved adherence adn relapse reduction

  • admin from q2weeks to 6 months (differ by drugs)

  • reserved for pts with severe acute schizophrenia adn for long term

• inhaled

EPS ADEtardive dyskinesia, may persists

• hours -days: acute dystonia, reversible

• days-weeks: akathisia, usually reversible

• week s- months: parkinsonism, usually reversible

• months-years: tardive dyskinesia, may persist

EPS- acure dystonia

• painful, sustained contractions

  • neck, jaw, face, back, oculogyric, laryngeal

• airway emergency risk→ eval urgently when respiratory sx, stridor, or severe neck/tongue spasm

EPS: akathisia

• inner restledssness with pacing, shifting; inability to stay still

  • MC EPS sx

how to treat akathisia

• reduce does of offending drug or switch, propanolol is 1st line, can consider benxo short term

• prevent: start low and go slowwwww

EPS: parkinsonism

• bradykinesia, rigidity/cogwheeling, resting tuor, mask liek facies, shuffling gait

how to treat EPS parkinsonism

• reduce dose of offending agent or switch, anticonlinergic (benztropine) or alternative amantadine (dopaminergic)

EPS tardive dyskinesia

• late effect, involuntary choreoathetoid mvmts, often irreversible

  • look for oro-facial dyskinesias (lip smaking, tongue protrusion, chewing) and

• MC with FGA

hwo to treat tardive dyskinesia

• stop offending agent and switch to another

• VMAT2 inihib (valbenazine) for sx mgmt

what antipsychotic has to lowest risk of TD

• clozapine

what type of meds worsen TD

anticholinergics

BBW on all antipsychotics

• increased ris kof mortality when used to Tx dementia- related psychosis in older adult pts

neuroleptic malignant syndrome (NMS)

• life threatening emergency- follows initiation or dose escalation

• risks increase with high potency FGAs

s/sx of NMS (FALTERED)

• fever

• autonomic insability

  • tachy, labile BP, tachypnea, disphoresis

• leukocytosis

• tremor

• elevated CPK

• rigidity (lead pipe)

• excessive sweating

• delerium/altered mental status

how to treat NMS

• stop drug

• + supportive care

• ± dantrolene for severe rigidity/hyperthermia or bromocriptine

NMS vs Seritonin syndrome

NMS

• gradual onset (few days)

• mod-severe muscle rigidity

• hyporeflexia

SS

• rapid onset (hours)

• hyperrefelxia

• tremors

• clonus

• midl muscles rigidity

BOTH

• fever

• altered mental

• autonomic instbaility

SGAs metabolic syndrome

• monitor at baseline and throughut tx

  • weight/BMI/waist circumference

  • fasting glucose/HbA1c

  • lipids

• also monitor for increase prolactin, QTc prolongation, sedation, EPS including TD throughout tx course

positive of clozapine

• treats tx-resistant schizophrenia

• reduces suicide risk

• lowest risk of TD

negatives of colozapine

• agranulocytosis

• myocarditis

• seizures

• severe constipation/ileus

• metabolic adverse effects

cloazapine boxed warning

• server neutroprnia

• orthostatic hypotension, brady, syncope

• seizures

• myocardiits, pericarditis, cardiomyopahty

• increased mortality i elderly pts

clozapien specific monitoring

• ANC: baseline and then per schedule throughout tx

  • weekly x6months, then q2weeks x6 moths, and then annually

• ANC<1000: HOLD

• ANC<500- agrnaulocytosis→ D/C

• monitor baseline and weekly troponin adn CRP for the first 4weeks

what to add to pt education when on cloazpine

• bowel regimen for GI hypomotility

psychoeducation

• realistic expectations abotu timeline for improvement

• risk of premature d/c no adherence

first inclass novel drug fo rschizophrenia

xanomeline-trospium

xanomeline-trospium MOA

muscarinic M1/M4 receptopr agonist

• xanomeline- selective muscarinic M1/M4 receptor agonist

• tropsium- peripherally acing muscarinic antagonist that mitigates the perioheral cholinergic ADRs of xanomeline

what is xanomeline-trospium effective for

• total and postive sx

  • effect on neg sx is promising but not consistent across trials

xanomeline-trospium common ADRs

relativley favorable safety profile

• constipaiton

• nausea

• dry. mouth

• dyspepsia

• vomiting

• urinary retntion

• dizzy

• coinfusion

• somnolence

• tachy/HTN

serious/rare ADE xanomeline-trospium

• angioedema

xanomeline-trospium monitoring

• periodic adn baseline

  • HR/BP, aminotransferases adn bili

greatest risk of EPS

FGA

what type of antipsychotic drugs are preferred

atypicals

antipsychotics with greatest risk of metabolic syndrome

atypiclas

antipsychotic metabolic side efefcts

• greatest risk: clozapine, olanzapine

• mod risk: rispereidone, quetiapine

• lowest risk: aripiprazole, brexpiprazole, caprazine

antipsychotics very sedating/good for insomnia

• quetiapine

• olanzapine

least sedating antipsychotics

• aripiprazole

• brexpiprazole

• cariprazone

• lumateprenone

antipsychotics ofr older pts

• lowest dose

• brexpiprazole specifically indicated for agitaiton with dementia secondary to AD

lomg QTc risk

• avoid ziprasidone, quetiapine, chorpromazine, IV aloperidol

antispychotic most likely to cause hyperprolactiemia

• risperidone

antipsychotic greatest risk of NMS

• FGAs

generally preferred initial FGA

• haloperidol

  • can caontrol positive sx at lower dose

  • generally better tolerability diue to less ANTI-HAM effects compared to pther FGAs

  • but more risk of EPS

when to move to clozapine

• inadequate response from 2 antipsychotics

expected response when treating schiz

• several days- start resoluti9on of psychotic sx

• 4-6weeks- for full improvement

• first 2weeks- most rapid imporvement

  • if only minimal response→ change

first line oral meds for acute agitation

• lorazepam

• haloperidol + lorazepam

• olanzapine

  • space doses further apart in women

first line injectable meds for acute agitation

• haloperidol + promethazine

• olanzapine

olanzapine ADE

• potentially ife threatening sedatioo adn hypotension when co admin with benzo

atypical antipsychotic drugs

• -pines

• -dones

• 2 pips

• rip

• adn new -rone

med classes for bipolar disorders

• mood stabilizers

• antipsychotics

• antidepressants

mood stabilizers- bipolar disorder

• lithium

• anticonvulsants

  • divalproex sodium/ valproic acid/ vaproate sodium

  • carbamazepine

  • lamotrigine

antipsychotics- bipolar disorders

• DGAs- olanzapine, risperidone

• can uie FGA

• note: some DGAs ar eFDA approved as asjunct fo runipolar major depressive disorder and other dx

antidepressants- bipolar disorder

• adjunt

• NEVER monotherapy in bipolar

biopolar disorders- targeting specific phase of tx

• treat acute mania.hypomania

• treat acute mixed episode

• treat acute bip[olar depression

• maintenance

• not all meds use din bipolar are effective in every phase

glutamiate meds

• lamotrigine→ decresaes glutamate release

• carbamazepine→ decreases glutamate release via Na channel blockade

GABA med

• valproic acid→ increased gaba activity

mania

• high energy state

• ± psychosis

• functional impairement

• surphoric moods, inflated slef esteem, decreased need for sleep, etc

hypomania

• mild version of manic sx

• no psychosis

• no functional impairement, or only minor imapirement

bipolar depression

• low energy state

• depressed mood, anhedonia, fatigue, executive dysfunction, worthlessness, insomnia or hypersomnia

• SI

mixed- bip0olar phase

• combo of manic and depressed sx

meds for acute mania

• lithium

• valproate

when treating, d/c destabilizers (eg. antidepressants)

med for acute bipolar depression

• lamotrigine

bipolar maintenence

• lithium

lithium MOA

• mitoifactorial, NT modulation, intracellular signaing inhibition, neuroprotective properties

• modulationergic of phosphoinositol pathway

  • dampens ascessive neuronal sxcitability primarily by reducing excitaory NT and increasing inhib GABA