Rx Antipsychotics

    Counselling Points

    1. This medication will help you feel calm
    2. It will help with sleep
    3. Will slow down and organize thoughts
    4. It will take away things a person hears, sees, and feels that aren’t there.
    5. It will help you cope with distressing fears (paranoia)
    6. 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

    -       Typical: Not mood stabilizing, poorly tolerated short term
    -       Atypical: Mood stabilizing (better short term)   (Study.. kaiti??)
    -       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”)
    1. Dystonias (spasm) in hours to 7 days  (extra Ach)
      1. Tx w/ anticholinergics (i.e. benztropine (Cogentin) 2mg or benadryl 25-50mg)
      2. Tx w/ benzos (lorazepam (ativan) 2mg)
    2. Restlessness (can’t sit still, restless) in hours to 14 days   (not explained by extra Ach, unknown)
      1. Benzos (lorazepam or clonazepam)
      2. B-blockers (if antipsychotic induced, anxiety disorders (i.e stage fright), mood stab. tremor) i.e. propranolol
      3. (Anticholinergics ineffective)
    3. Pseudoparkinsonism  (too much Ach: cogwheel tone, mask faces etc.)within 30 days
      1. Anticholinergic (Benztropine (Cogentin), Benadryl)
    4. 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)
    1. 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
      1. Can treat by increasing offending agent, but comes back worse
      2. Usually stop offending agent, can go away over time
      3. High-dose benzos (clonazepam)
      4. AchE inhibitors, may or may not work (Donepezil)
      5. Clozapine (does not cause TD, actually fixes it)
    1. Tardive Akathisia (restlessness)
      1. (see tardive dystonia)
    2. Tardive Dystonia
      1. Sx similar to acute form
      2. Not understood why
      3. 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.
    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

    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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