Psychoses and Antipsychotic drugs stupor

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					Psychoses and Antipsychotic drugs
Psychoses—group of mental disorders characterized by rifts in rational thought, inappropriate processing of
sensory information, and disturbed views of reality and self. Psychotic symptoms are generally not recognized
as such by the sufferer. (abnormal reactions, which the patient doesn’t know are abnormal; think self is affected
by outside force)

Neuroses—abnormal reaction to an external state that is generally recognized as abnormal by the sufferer.
(schizophrenic thinks self is affected by something wrong with him/herself)

Schizophrenia—disease characterized by severe psychotic symptoms present for at least 6 months (present in
people from late teens to 30’s)
         Delusions (breaks in reality) and/or paranoia (fear everything)
         Prominent hallucinations—auditory most commonly
         Disordered thoughts/loose ideation (thoughts are disconnected)
         Flat affect (no matter what emotional event, they don’t express emotion)/anhedonia (inability to find joy
in life)
Notes: can’t appropriately process external noises, information. (ex. sound from the overhead projection, brain
tries to turn it into something logically in an individual with schizophrenia, whereas a normal person would
ignore it)
Schizophrenics try to make sense of all sensory input
Predictors of schizophrenia
     1) illegal use of drugs before age 9
     2) gambling problem before age 21

“Positive” symptoms (“overt” actions, like washing hands if they think
blood is always on their hands)
Irritational thoughts
Bizarre and/or repetitive behaviors
Agitation, aggression, restlessness
(drugs can treat)

“negative” symptoms (lack of things)
blunted or inappropriate affect
apathy, anhedonia, lack of motivation
poverty of speech
(drugs harder to treat with)

Prodromal signs and residual disease manifestations precede and persist between full-blown episodes

Synesthesia—“screwed up” perception caused by crossing of sensory inputs.

Incidence and disease statistics
=1% of the population in the U.S.
men and women equally affected
age of onset from 15-25 years
high mortality rate (10%), poor longterm prognosis
Possible etiologies
Genetic and environmental factors are involved
       Predisposition substantiated by twin studies
       Increased incidence of perinatal insults among schizophrenic patients

Associated anatomical/functional irregularities
Enlarged ventricles, abnormal widening of cortical fissures
Decreased cortical tissue mass
Inappropriate startle reflexes and poor visual tracking in schizophrenics and unaffected close relatives

Subtypes of schizophrenia
    Schizoaffectivce disorder (combination of schizophrenia with depression)
    Schizophreniform disorder
    Paranoid schizophrenia
    Multiple personality disorder
    Schizotypal personality disorder (less severe than schizophrenia)

Psychoses in other disease states
    Delirium in dementia
    Manic psychoses
    Psychotic symptoms secondary to severe depression
    Drug-induced psychosis
          o Amphetamine psychosis
          o PCP and ketamine overdose

Treatment options
Lobotomy (severing prefrontal cortex of brain)
            Used extensively in the 1940s and 1950s to control antipsychotics patients
            Pacified florid psychotics
            Permanently debilitated most patients (vegetative state)

Psychotherapy and behavior therapy
      Psychotherapy (interpersonal or “talk” therapy) alone is NOT very effective

       Behavioral therapies may alleviate symptoms
             Maintain basic personal hygiene
             Social skills or daily living skills instruction

       75-90% of schizophrenics smoke tobacco
       may increase the efficacy of haldol

      Most effect means of treating symptoms of psychosis
Antipsychotic drugs
Antipsychotics, neuroleptics, antischizophrenics, or major tranquilizers-synonyms
Most effective against “positive” psychotic symptoms

NOT anesthetics
      But, may potentiate anesthesia (but no loss of consciousness)
Latency of effectiveness
      Calming (tranquilizing) effects may be seen within minutes to hours
      Full antipsychotic effects require 2-6 weeks, on average
      Improvement may continue for up to 6 months
Used chronically to prevent relapse

Effective in 70% of psychotic patients
       Predictors of responsiveness
               Later age of onset
               Normal functioning prior to initial onset of disease
               Lack of brain abnormalities (normal ventricles)
               Normal levels of HVA in urine

Dopamine hypothesis of schizophrenia
      Reserpine, which depletes nerve terminals of biogenic amines, is an antipsychotic (depletes NE, EPI,
       DA sources)
      Chronic amphetamine and cocaine adminstration can produce paranoid psychoses (blocks reuptake of
       catecholamines and dopamine)
      Density of D2 dopamine receptors is elevated (by almost 2 fold) in a large number of schizophrenic
       brains post-mortem.
      Antipsychotics produce movement disorders reminiscent of Parkinson’s disease
      Antipsychotic affinity for “D2”-like receptors correlates with potency to reduce symptoms

Antipsychotics have a very rich pharmacology
       All are dopamine D2 family (D2, D3, D4) receptor antagonists or weak partial agonists
              D2 family receptors inhibit adenylyl cyclase
              D1 (D1, D5) family receptors activate adenylyl cyclase
       Note: antipsychotics will decrease schizophrenic symptoms, but create more Parkinson-like symptoms.
       Dopaminergic pathways (review)
              Mesolimbic and mesocortical pathways
                     Mesencephalon VTA projects to limbic areas and cortex, including prefrontal cortex
                     Positive symptoms of schizophrenia may be mediated by overactivity of mesolimbic
                     projections, particularly through activation of D2, D3, and/or D4 receptors
                     Negative symptoms may be mediated by problems with mesocortical projections,
                     particularly through activation of D1 receptors or 5-HT2 receptors

               Tuberoinfundibular (tuberohypophyseal) pathway
                     D2 receptors inhibit prolactin release from lactotrophs

               Nigrostriatal pathway
                      Predominantly D1 and D2 receptors post-synaptically (notably little D3, D4, and D5)
                      Antagonism of D2 receptors produces extrapyramidal side effects (EPS) (so you give a
                      muscarinic antagonist to decrease the EPS like benzotropine, procyclidine)
                      Overactive in Tourette’s syndrome
                      Selectively degenerated in Parkinson’s disease

Newer agents are also serotonin receptor antagonists
      Fewer movement side effects with newer agents
             5-HT2 antagonists seem to selectively modulate dopamine transmission in the nigrostriatal
             pathway, lessening movement side effects
      Must be in combination with D2 receptor antagonism
             Purely selective 5-HT2 antagonists are not very good antipsychotics
      Efficacy against hallucinations may be related to 5-HT2 antagonism
             LSD, a 5-HT2 receptor partial agonist, causes hallucinations and synesthesia (stimulation of one
             sense causing the response of another)
      5-HT2 antagonism may also help to improve negative symptoms

Most antipsychotics are also histamine, muscarinic, and adrenergic
receptor antagonists of varying affinities
Typical neuroleptics (a short selection of a large group)
       Phenothiazines and related thioxanthines
              Chlorpromazine (Thorazine®), the grandparent of all antipsychotics
              Theoridazine (Mellaril®), Fluphenazine (Prolixin®)
              Thiothixene (Navane®)
       Butyrophenones and related compounds
              Haloperidol (Haldol®), Droperidol, Pimozide (Orap®)

Newer atypical neuroleptics (fewer EPS)
              Clozapine (Clozaril®), Loxapine (Loxitane®), Olanzapene (Zyprexa®), Quetiapine (Seroquel®)
              Risperidone (Risperdol®), Ziprasidone (Geodon®), Molindone (Moban®), Aripiprazole

Toxic dose-limiting effects
Extrapyramidal side effects (EPS)
Acute dyskinesias
             Motor restlessness and distress that is unique to humans and compels constant movement
             including an inability to remain sitting
             May be difficult to distinguish from psychotic agitation

             Spasms of neck and face muscles including grimacing, torticollus (spasms of head and neck
             muscles), ocular dysfunction
             Involuntary and frequently painful movements and bodily distortions

       Parkinson syndrome
              Not Parkinson’s disease, looks similar
              Bradykinesia, rigidity and resting tremor of head and hands, loss of facial expressiveness
EPS are frightening to patients
       More common in older patients
       More common in women
Sometimes confused with underlying psychotic symptoms
Most commonly seen with high dose bolus or initial depo injection
Treat by decreasing dose
Muscarinic receptor affinity is inversely correlated with EPS

Muscarinic receptor affinities of selected antipsychotics with EPS
Drug                          Kd (nM)                        Frequency of EPS
Thioridazine                  25 (highest affinity)          + (least EPS)
Clozapine                     55                             +
Chlorpromazine                350                            +++
Promazine                     160                            ++
Trifluoperazine               4000                           ++++
Flupenthixol                  2200                           ++++
Spiroperidol                  12,000                         ++++
Haloperidol                   16,800 (lowest affinity)       ++++ (highest EPS)

Negative feedback circuitry in the extrapyramidal motor system
   1.   dopamine neurons from the substantia nigra synapse on D2 receptors in the striatum
   2.   D2 receptors are inhibitory on cholinergic interneurons in the caudate
   3.   Cholinergic interneurons synapse on excitatory muscarinic receptors on GABAergic neurons
   4.   GABAergic neurons return to the substantia nigra and synapse on GABAergic interneurons
   5.   GABA is inhibitory to the GABAergic interneurons
   6.   GABAergic interneuron inhibits the firing of the dopamine neuron in step 1

              Circuitry designed for negative feedback to avoid excessive firing of the dopamine neurons
              In the presence of a D2 antagonist, cholinergic interneuron increases firing, negative
               feedback decreases and motor activation increases (ultimately)
              Add a cholinergic antagonists to the D2 antagonist and the system re-stabilizes
               CNS active muscarinic antagonists (eg. benztropine) may be helpful

Adverse effects of antipsychotics
Short term effects (weeks to months)
Weight gain
       May be linked to alpha-1 antagonism at the level of the hypothalamus
       Appetite is increased as well fat storage can lead to significant increases in body mass
       Linked to increased type incidence of type II diabetes and heart problems

Drowsiness and sedation
      Related to antagonism of H1 receptors by both typical and atypical antipsychotics

Dry mouth, constipation, urinary retention, blurred vision, confusion and memory loss
      Antagonism of cholinergic receptors
             May help to decrease extrapyramidal side effects
      More problematic in older patients

Hypotension and reflex tachycardia
      Antagonism of alpha-1 adrenergic receptors
      Particularly problematic with chlorpromazine which has significant cardiotoxicity
      More problematic in older patients
Endocrine disruptions
      Gynecomastia and increased lactation
              Attenuation of D2 inhibition of prolactin release at pituitary lactotrophs
      Disturbed thermal regulation (hypo/hyperthermia)
      Amennorhea, infertility, and sexual dysfunction
              Prolactin suppression of fertility and sexual urges

Hypersensitivity reactions
      Photochemical reaction associated with chlorpromazine and phenothiazines in 5% of the population,
      manifests 2-4 weeks after initiation of therapy
      Dermal reactions including sun sensitivity

Potentially fatal adverse effects
             Typical neuroleptics linked to increased risk of sudden cardiac death
             Contraindicated with heart disease
                     Muscarinic and alpha-1 adrenergic antagonist activity combine to produce problems with
                     Direct and reflex tachycardia
             Prolonged QT interval may cause fatal arrythmias (Torsades de pointe)
                     Increased 40 msec on average, 100 msec increase leads to arrythmias
                     Linked to typical and atypical neuroleptics
                     Contribution to sudden cardiac death associated with antipsychotics?

Neuroleptic malignant syndrome
       Rare but potentially fatal (10% mortality rate) syndrome associated with both typical and atypical
       May be recurrent

             Hyperthermia and diaphoresis
             Tremor and muscle rigidity
             Altered mental status, including catatonia and stupor
             Hypotension and tachycardia, or fluctuating blood pressure and pulse
             Acute renal failure

             Immediate discontinuation of all antipsychotic medication

              Dantrolene may be helpful for unknown reasons

              Bromocriptine, a dopamine agonist, may be helpful in large doses L-dopa is NOT effectivec
Longterm effects (>1 year)
       Tardive dyskinesia
              Occurs in 50% of patients treated with antipsychotics
              Severity is related to dose, duration of treatment, and gender (women are more prone to tardive
              Related to supersensitivity of D2 dopamine receptors in the striatum following longterm
              antagonist exposure

              Develops after tolerance to extrapyramidal side effects

                     Involuntary, slow, writhing movements of the face and tongue
                     Smacking of the lips
                     Tongue protrusions
                     Chewing and lateral jaw movements
                     Withdraw or reduce dose of antipsychotic medications
                     Increase the dose of antipsychotic?
                     Administer a cholinomimetic??
                     Vitamin B6 supplements (100 mg pyridoxine / day)

Atypical antipsychotics
       Recommended by the American Psychiatric Association as firstline therapies in schizophrenia.
              Lowered incidence of EPS
              Much higher costs of these drugs
       All have higher 5-HT2 than D2 affinity
       Incidence of EPS may be related to “occupancy” of D2 receptors in the absence and presence of a
       Spike of dopamine
              “classic” antipsychotics block all dopaminergic transmission
              atypical antipsychotics with low EPS potential may release during a high spike of dopamine
              The “newest” atypical agent is a dopamine partial agonist

Clozapine (Clozaril ®)
       Uniquely effective in 30-50% of treatment-resistant patients
       Highest efficacy of any antipsychotic??
       Lowest incidence of EPS
       Very promiscuous drug and associated with multiple side effects
       High affinity for muscarinic receptors
              Anticholinergic side effects are problematic
              Contributes to lack of EPS
       Selectivity for D4 receptors over D2 receptors
              Antagonism of D4 receptors in limbic system may improve antipsychotic activity
       Spares the D2 receptors in the striatum and pituitary

       High affinity for 5-HT2 receptors
       High affinity for histamine receptors
       High affinity for alpha-1 receptors
       Unique and potentially fatal adverse effects
       Reduction of seizure threshold
       Agranulocytosis and bone marrow suppression

Risperidone (Risperdol ®), approved since 1994
       Marketed as a drug with effectiveness against negative as well as positive symptoms
       D2, 5-HT2, and alpha-1 antagonist
              Moderate weight gain

       Low affinity for H1 and alpha-2 receptors
       No affinity for muscarinic cholinergic and D1 receptors
              Fewer unpleasant anticholinergic effects
              Low incidence of EPS at low doses (6 mg per day), 10-16 mg/day will cause EPS

       Prolongs QT interval

Olanzapine (Zyprexa ®), approved since 1996
      Structurally related to Clozapine
      Somewhat effective in treatment-resistant patients but may not be quite as effective as clozapine
             Similar pharmacologic and side effects profile to clozapine
             Affinity for D1 receptors
      No agranulocytosis
      No reported cardiotoxicity

Quetiapine (Seroquel ®), approved since 1997
       Relatively lower D2 affinity
              Low incidence of EPS and endocrine disruptions
       No agranulocytosis or hematologic changes
       No antimuscarinic activity
       H1 and alpha-1 antagonist side effects include sedation and weight gain

Ziprasidone (Geodon ®), approved in 2001
       5-HT1a agonist
       Has moderate affinity for NET and SERT
             May have some antidepressant properties in addition to antipsychotic properties
             Antidepressants are often mixed with antipsychotics to improve patient responsiveness
       Low affinity for alpha-1, histamine, and D1 receptors
       Prolongs QT interval

Aripiprazole (Abilify ®), approved in 2002
      Dopamine/serotonin “system stabilizer”, ie partial agonist
              D2 partial agonist
              5-HT1A partial agonist
              5-HT2 antagonist
              alpha-1A antagonist
      Efficacy comparable to Haldol
      Low endocrine disturbances
              Slight decrease in prolactin secretion
      Little to moderate weight gain, low sedation, no QTc prolongation
Additional indications for neuroleptic drugs
Neuroleptanalgesia (Innovar ®) and neuroleptanesthesia
       Droperidol (a butyrophenone) is used in combination with opioid analgesics (fentanyl)
       Concurrent administration of N2O produces neuroleptanesthesia

Tourette’s syndrome
      Uncontrollable vocal outbursts with repetitive movement problems, tics, uncontrollable facial
      Too much dopaminergic activity in the nigrostriatal pathway
      Treat with a high affinity, highly selective D2 antagonist
              Pimozide (Orap®) is currently approved

Prevention of severe nausea and vomiting
      Antagonism of D2 receptors suppresses the chemoreceptor trigger zone of the medulla
      Anti-histamine and anticholinergic effects contribute to anti-nausea efficacy
              Prochlorperazine (Compazine ®), discussed with GI drugs, is often used
      Not suitable for nausea due to vertigo, motion sickness, or pregnancy

Intractable hiccups
Insufficient lactation
       D2 receptor antagonists will inhibit the D2 inhibition of prolactin release from pituitary lactotrophs
               Metoclopramide (Reglan ®) may be used. Domperidone is another possibility.

Bipolar disorder
       Recurrent illness in which patients oscillate between depression and mania
             Affects 1-2% of the US adult population, men and women equally from 18-45 yers.
             Has a genetic component

       Symptoms of mania include:
            Persistently elevated mood and extreme extrovertedness (opposite of shyness)
            Exaggerated sense of self-importance leading to delusions of grandeur
            Fearlessness, engagement in high-risk, thrilling behaviors (sky-diving)
            Poor impulse control (gambling, over-spending)
            Excessive libido
            Verborrhea (rapid and continuous speech), racing thoughts and distractibility
            Hyperactivity, insomnia, irritability and impatience that can lead to paranoia

       Bipolar disorder has cycles of depression and mania with a periodicity of days/weeks to months
             Manic phase typically lasts one week but may be proceeded by weeks or months of hypomanic
             Depressive phase may last much longer (several months) and is characterized by extreme inertia
             and apathy
             Rapid cyclers are difficult to treat and stabilize

       Drug treatments for simple depression and bipolar disorder are distinct
             Antidepressant medications can precipitate a manic phase
Treatment of bipolar disorder
Lithium carbonate
      Inorganic cation, excreted in urine unmetabolized
      Most effective treatment in bipolar disorder
             Effective in 80% of manic attacks within 1-2 weeks
             Problems with toxicity must be considered with need for efficacy
      No effect in normal subjects
      Used prophylactically to prevent mood swings and cycling into a manic phase
      Mode of action is still poorly understood
             May increase uptake of 5-HT and NE
             Partially inhibits tryptophan hydroxylase
                     May inhibit 5-HT synthesis and release
             Blocks inositol-1-phosphatase activity D
                     Decreases recycling of IP3 and production of PIP2, ultimately inhibiting PLC activity
             Blocks glycogen synthase kinase 3
                     Nexus for pathways linked to neurotrophic support, neuroprotection, circadian rhythms
                     GSK3 mediates amphetamine-induced hyperactivity in mice, a model of mania.

Lithium substitutes for Na+ and Mg++, but is less efficient
       Accumulates in excitable cells and disrupts action potentials
       Low therapeutic index (~2)
Adverse effects that decrease over time
       Nausea, vomiting
       Muscle weakness and fatigue
Persistent adverse effects
       Hand tremors (sometimes very debilitating)
       Polydipsia and polyuria
               Maintain normal sodium intake as Na+ deficiency increases lithium toxicity
               Regulate water intake
               Contraindicated with compromised renal function
               Hypothyroidism in some patients
Toxicity at slightly higher doses
       Ataxia and slurred speech
       Confusion and disorientation
Overdose toxicities
       Muscle rigidity, deep tremor
       Cardiac arrythmias
       Coma and death
Anti-convulsants used as “mood stabilizers”
    Not as effective as lithium, but not as toxic
    Onset of action is much quicker than lithium
    Mode of action probably related to general CNS inhibition
    Problems include weight gain, sleepiness, and inability to concentrate

Valproic acid, divalproex (Depakote®) and clonazepam
Carbamazepine (Tegretol®)
    Tricyclic compound related to imipramine with a weak affinity for SERT

Topiramate (Topamax®)
    Fewer problems with weight gain
    May induce a rare type of closed angle glaucoma

    Used as mood stabilizers
    Dosage for treating bipolar disorder is often much less than for schizophrenia
    Mode of action may be related to inhibition of serotonin receptors in combination with anti-histamine-
    related sedating effects.

Benzodiazepine sedatives
    Rapid efficacy
    Not a long term treatment option

Combination treatments
    Symbax ® -- Zyprexa ® and Prozac ®

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Description: Psychoses and Antipsychotic drugs stupor