Counselling Points
- This medication will help you feel calm
- It will help with sleep
- Will slow down and organize thoughts
- It will take away things a person hears, sees, and feels that aren’t there.
- It will help you cope with distressing fears (paranoia)
- ATYPICAL: It will balance the mood and prevent mood swings.
Antipsychotics Overview (7)
Clozapine (Clozaril)
- For refractory schizo, very strong, prevents SI, but high risk agranulocytosis (need frequent blood work.), high risk of myocarditis, constipation, seizures. Drooling?
- NO short/long term movement disorders, actually fixes tardive dyskinesia (see below).
- Highest incidence of diabetes, wt gain, choelsterol
Olanzapine (Zyprexa) Start 5mg (10-20mg maint)
Quetiapine (Seroquel) Start: 50mg (Dose: 150-300mg)
- Does not cause tardive dyskinesia
- Low doses, anxiety, sleep (not as good as Olanz and Respiradone)
- Low anticholinergic (can use in elderly...risperidone is better though)
Risperidone (Risperdal) Start 2mg work up to 4-8 maintenance (elderly: 1mg)
- Clean, good s/e profile (some wt gain, chol ok, low diabetes), not anticholinergic. Can use in delirium dementia. (too much antichol. in elderly causes delirium.. In kids: euphoria, so avoid others)
- Depo available
Paliperidone (Invega) (Sustenna monthly depot injectable)
- Metabolite of risperidone, advantage not clear.
- Depo available
Ziprasidone (Zeldox)
- very low metabolic issues.
Aripirazole (Abilify) (3rd gen atypical)
o Newest…good pharmacology, doesn't seem to work.
Less S/E
Others are Typical
Chlorpromazine (Largactil) (also anti-Ach, less movement disorders)
Flupenthixol (Fluanxol)
Haloperidol (Haldol)
Loxapine (Loxapac) 25mg for acute psychosis (with 2mg ativan)
Many others....
Typicals vs. Atypicals
Therapeutic
- Typical: Not mood stabilizing, poorly tolerated short term
- Atypical: Mood stabilizing (better short term) (Study.. kaiti??)
Administration
- Typical: Lots of IV forms available (SA + LA)
- Atypical: Few injectable forms (only olanzapine IM, SA only)
Side Effects:
- Typical: Tardive syndromes (Tardive dyskinesia)
- Atypicals:
o Metabolic S/E: +++ wt gain, cholesterol, incr risk of diabetes independent of wt gain.
o Metabolic S/E: (worst) clozapine<------------------->Aripiprazole (best)
- Both typicals and atypicals equally effective in schizophrenia (except clozapine is at treating positive sx and maybe even treats negative (no others due))
Mechanism (Dopaminergic Pathways)
Dopaminergic Pathways
1. Mesolimbic
· Emotions originate
· Too much DA causing +’ve sx (delucions/hallucinations)
2. Anterior cortical
· Emotions managed
· Too little DA causing –‘ve sx and cognitive impairment (memory, executive functioning)
· (Block dopamine here does not improve negative/cognitive sx)
3. Nigrostriatal
· Achieve smooth movement provided inhibitory Ach (no go) and excitatory dopamine (“go”) are in balance
· Block dopamine causes D2<Ach – movement jerky and stiff (Parkinsonism)
· Long term blockade causes incr in D2 receptors – tardive sx.
4. Tuberoinfundibular
· Connects hypothalamus to anterior pituitary
· (prolactin + thermoregulation)
· Blocking D2 causes:
- Hyperprolactinemia
· Women: galactorrhea, amenorrhea, decr libido
· In men: decr libido, erectile dysfunct, gynecomastia
Not on test, sidebar:
Newest theory: take PCP mimics schizophrenia, hence the NMDA glutamate theory
- PCP or ketamine closes NMDA (glutamate closes)
- Clozapine works best, may tinker with NMDA receptor
How they work
All drugs block D2 (treats +’ve sx), but do not tx –‘ve sx or maybe even worsen
Typicals – Block D2
- Block D2, which increases Ach in Basal ganglia – parkinsonism (same as Parkinson, except in parkinson’s dopaminergic neurons die)
- Basal Ganglia – outside pyramids (EPS)
- To fix this use anticholinergic
- After 4-5 year use can get tardive dyskinesia – writhing, shaky – too much movement
o NOT parkinsonian b/c it’s similar to “cocaine walk” “crack walk” due to extra dopamine
o TD is similar b/c too much DA, and tissue grows more D2 receptors over time
Atypicals – Block D2 and 5-HT2
- Serotonin blockade is presynaptic, causes release of dopamine which displaces antipsychotic from D2 receptor (reverses itself).
- However few 5-HT2 receptors in mesolimbic pathway, so most D2 blockade there
- Therefore, dopamine blocked in mesolimbic, and unblocked in others (and potentially improves dopamine and helps negative, cognitive, and hyperprolactinemia, stiffness/jerky movements, and tardive dyskinesia in theory)
o However CATIE I trial showed limited benefits, but old inexpensive trials may not be accurate. Atypicals probably better tolerated.
- 5HT2C also blocked – appetite incr (metabolic sx) (clozapine worst)
- Also sedating, relaxing by blocking 5HT2C and 5HT2A
- Causes Incr appetite, but mechanism of impaired blood sugar and dyslipidemia in absence of weight gain not understood.
Side Effects
Short-Term Movement Disorders
(For S/E: can reduce dose, change antipsychotic, in addition to tx listed)
- Dopamine (“go”) < Acetylcholine (“no go”)
- Dystonias (spasm) in hours to 7 days (extra Ach)
- Tx w/ anticholinergics (i.e. benztropine (Cogentin) 2mg or benadryl 25-50mg)
- Tx w/ benzos (lorazepam (ativan) 2mg)
- Restlessness (can’t sit still, restless) in hours to 14 days (not explained by extra Ach, unknown)
- Benzos (lorazepam or clonazepam)
- B-blockers (if antipsychotic induced, anxiety disorders (i.e stage fright), mood stab. tremor) i.e. propranolol
- (Anticholinergics ineffective)
- Pseudoparkinsonism (too much Ach: cogwheel tone, mask faces etc.)within 30 days
- Anticholinergic (Benztropine (Cogentin), Benadryl)
- Others (Rabbit syndrome, Pisa syndrome)
Long-term Movement Disorders
- post-synaptic D2 receptors upregulate + more DA released presynaptically, reversing the nigrostriatal neurotransmitter balance.
- Dopamine > Acetylcholine = Excess of “go” signal
Over time, short-term S/E reverse (D2 upregulated causing too much dopamine, can increase ach to balance it)
- Tardive Dyskinesia Months to years of tx (>90days) - extrapyramidal... snaky movements
3-5%/year for typicals and 0.2-0.5% for olanzapine, 0% clozapine
Often irreversible, even if discontinue, less reversible with age
-
- Can treat by increasing offending agent, but comes back worse
- Usually stop offending agent, can go away over time
- High-dose benzos (clonazepam)
- AchE inhibitors, may or may not work (Donepezil)
- Clozapine (does not cause TD, actually fixes it)
- DO NOT USE ANTICHOLINERGICS
- Tardive Akathisia (restlessness)
- (see tardive dystonia)
- Tardive Dystonia
- Sx similar to acute form
- Not understood why
- both very hard to treat, can try botox with dystonia
Neuroleptic Malignant Syndrome
- Pathophysiology unclear, but prob a sudden decrease in dopaminergic transmission
- Antipsychotic use (block dopamine) or sudden withdrawal of dopaminergic (levodopa/carbidopa)
- Mortality 5-20%, often renal failure
- Onset early in tx but can happen late, evolve 2 to 9 days.
Symptoms:
Acute Severe Parkinsonism
- FARM
o Fever
o Autonomic instability (unstable heart rate, bp, sweating, drooling)
o Rigidity
o Mental Status Changes
- Delirium
- Immobility
- Mutism
- Tremor
- Labs: Leukocytosis, rhabdo, low Ca, Low Fe, elevated creatinine in late stages
- Tx: D/c antipsychotic, antipyretics, benzos, bromocriptine (Parlodel) Dantrolene (Dantrium)
Serotonin Syndrome
- Sudden excess of serotonin
- Classically mixing MAO inhibitors with SSRIs
- Symptoms
- Fever
- Encephalopathy (agitation)
- Rigidity
- Hyperreflexia
- Clonus, Hypertension, Hyperactive bowels
- Drugs:
- Serotonergic
- Treatment:
- Benzos
Special Topic: Anticholinergics
- Decreasing anticholinergic potency
o Trihexyphenidyl (Artane)
o Benztropine (Cogentin)
o Procyclidine (Kemadrin)
o Diphenhydramine (Benadryl)
o Dimenhydrinate (Gravol)
- All equal effectiveness for acute dystonias, except Gravol
- Can inhibit dopamine reuptake, causing euphoria and stimulation (bupropion, cocaine)
- S/E:
o Elderly risk of delirium
o Blurred vision, dry mouth, constipation, urinary retention
o Dilated pupils
o Dry-flushed skin
o Tachycardia
- Anticholinergic excess: confusion, disorientation, hallucinations, incoherence
Antipsychotic Drugs Detail
| Haloperidol | Risperidone | Olanzapine | Quetiapine |
Sedation | <2 | 10 | 30 | 20 |
Anticholinergic | <2 | <2 | 30 | 20 |
Orthostasis | <2 | 30 | <2 | 10 |
Extrapyramidal | >30 | 10 | <2 | <2 |
Extrapyramidal: dopamine blockade (parkinsonism) stiff, cogwheel rigidity, mask facies, postural instability, tremor
- Clozapine (Clozaril)
o First antipsychotic
o Very effective for positive and maybe even negative sx, likely most effective in refractory schizophrenia
o Causes agranulocytosis (1%), removed from market, but then put back b/c useful drug. Need frequent blood monitoring
o Treats TD, does not cause TD
o Reduces suicide risk
o S/E:
1. Agranulocytosis (1%)
2. Lipid dysregulation
3. Blood sugar and diabetes
4. Severe wt gain
5. Myocarditis (tachycardia)
6. exacerbation of new onset obsessive behaviour
7. seizures (3-5% >600mg/day)
8. anticholinergic
· blurry vision, constipation, urinary hesitancy, but drooling b/c of M4 antagonist.
o Smokers usually have decreased plasma drug
- Olanzapine (1990s) (Zyprexa)
o Tx mood sx and positive sx.
o CATIE 1: longest time to “all-cause med discontinuation” among atypicals
o CATIE II: most effective after clozapine
o S/E:
o *Metabolic effects (not as bad as clozapine)
o mild-anticholinergic (blurry vision, dry mouth, constipation, urinary retention)
o Ortho hypotension (milder than clozapine)
o Sedation (milder than clozapine)
o Acute movement disorders: mild at high doses.
o low rates of TD, but does not tx it.
- Quetiapine (Seroquel, Seroquel XR)
o Less effective antipsychotic
o Metabolic effects less than olanzapine at low doses, and same at high doses.
o Anticholinergic, orthostatic hypotension, sedation, TD rare, not treat it.
- Risperidone (Risperdal)
o Haloperidol with 5HT2 blocking properties
o Very effective
o Metabolic effects – intermediate
o No anticholinergic effects
o Acute movement disorders – highest risk among atypicals
o TD – highest among atypicals, but lowest among typicals
o Sedation/insomnia, orthostatic bp, stuffy nose
- Paliperidone (2007) (Invega)
o Metabolite of risperidone
o Less a1 blockade? So less orthostatic, sedation, stuffy nose? maybe
o But polymorphisms in P450 2D6….so hard to dose???
- Ziprasidone (Zeldox)
o Related to risperidone
o However need bid dosing, and each with food
o No metabolic concerns
o Highest risk of QT prolongation
o Better S/E profile than risperidone
- Aripiprazole 2009 (Abilify)
o 3rd generation, chemically distinct
o Partion D2 agonist and other receptors, potent 5HT2A blockade
o No significant metabolic concerns (mild wt loss!)
o Great S/E profile, mildly activating (minimal acute movement disorders, minimal TD, insomnia, anxiety, agitation, N/V)
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