DRUG TREATMENT OF PSYCHOSIS

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DRUG TREATMENT OF PSYCHOSIS
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Psychosis

• Psychosis is a thought disorder characterized by
  disturbances of reality and perception, impaired
  cognitive functioning, and inappropriate or
  diminished affect (mood).
• Psychosis denotes many mental disorders.
• Schizophrenia is a particular kind of psychosis
  characterized mainly by a clear sensorium but a
  marked thinking disturbance.

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Psychosis Producing Drugs

• Levodopa
• CNS stimulants
• Cocaine
• Amphetamines
• Khat, cathinone, methcathinone
• Apomorphine
• Phencyclidine

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Schizophrenia

• Pathogenesis is unknown.
• Onset of schizophrenia is in the late teens early
  twenties.
• Genetic predisposition -- Familial incidence.
• Multiple genes are involved.
• Afflicts 1 of the population worldwide.
• May or may not be present with anatomical changes.

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Schizophrenia

• It is a thought disorder.
• The disorder is characterized by a divorcement
  from reality in the mind of the person
  (psychosis).
• It may involved visual and auditory
  hallucinations, delusions, intense suspicion,
  feelings of persecution or control by external
  forces (paranoia), depersonalization, and there
  is attachment of excessive personal significance
  to daily events, called ideas of reference.

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Schizophrenia

• Positive Symptoms.
• Hallucinations, delusions, paranoia, ideas of
  reference.
• Negative Symptoms.
• Apathy, social withdrawal, anhedonia, emotional
  blunting, cognitive deficits, extreme
  inattentiveness or lack of motivation to interact
  with the environment.
• These symptoms are progressive and non-responsive
  to medication.

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Etiology of Schizophrenia

• Idiopathic
• Biological Correlates
• Genetic Factors
• Neurodevelopmental abnormalities.
• Environmental stressors.

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Etiology of Schizophrenia

• Schizophrenia is not characterized by any
  reproducible neurochemical abnormality. However,
  structural and functional abnormalities have been
  observed in the brains of schizophrenic patients
• Enlarge cerebral ventricles.
• Atrophy of cortical layers.
• Reduced volume of the basal ganglia.

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Dopamine Theory of Schizophrenia

• Many lines of evidence point to the aberrant
  increased activity of the dopaminergic system as
  being critical in the symptomatology of
  schizophrenia.

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Dopamine Theory of Schizophrenia

• Dopamine Correlates
• Antipsychotics reduce dopamine synaptic activity.
• These drugs produce Parkinson-like symptoms.
• Drugs that increase DA in the limbic system cause
  psychosis.
• Drugs that reduce DA in the limbic system
  (postsynaptic D2 antagonists) reduce psychosis.
• Increased DA receptor density (Post-mortem, PET).
• Changes in amount of homovanillic acid (HVA), a
  DA metabolite, in plasma, urine, and CSF.

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Pharmacodynamics

• Anatomic Correlates of Schizophrenia...

• Areas Associated with Mood and Thought Processes

Frontal cortex Amygdala Hippocampus Nucleus
accumbens Limbic Cortex
DA DA DA DA DA
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Dopamine Theory of Schizophrenia

• Evidence against the hypothesis
• Antipsychotics are only partially effective in
  most (70) and ineffective for some patients.
• Phencyclidine, an NMDA receptor antagonist,
  produces more schizophrenia-like symptoms in
  non-schizophrenic subjects than DA agonists.
• Atypical antipsychotics have low affinity for D2
  receptors.
• Focus is broader now and research is geared to
  produce drugs with less extrapyramidal effects.

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Dopamine System

• There are four major pathways for the
  dopaminergic system in the brain
• The Nigro-Stiatal Pathway.
• The Mesolimbic Pathway.
• The Mesocortical Pathway.
• The Tuberoinfundibular Pathway.

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THE DOPAMINERGIC SYSTEM
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Catecholamines

• Tyrosine
• ? Tyrosine hydroxylase
• L-Dopa
• ? Dopa decarboxylase
• Dopamine (DA)
• ? Dopamine ? hydroxylase
• Norepinephrine (NE)
• (Noradrenaline) Phenylethanolamine-
• ? -N-methyltransferase
• Epinephrine (EPI)
• (Adrenaline)

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Tyrosine
Dopamine Synapse
Tyrosine
L-DOPA
DA
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Dopamine System

• DOPAMINE RECEPTORS
• There are at least five subtypes of receptors
• Receptor
• D1
• D2
• D3
• D4
• D5

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Dopamine System

• DOPAMINE RECEPTORS
• Receptor 2o Messenger System
• D1 ?cAMP
• D2 ?cAMP,?K ch.,?Ca2ch.
• D3 ?cAMP,?K ch.,?Ca2ch.
• D4 ?cAMP
• D5 ?cAMP

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Dopamine Reuptake System
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Antipsychotic treatments

• SCHIZOPHRENIA IS FOR LIFE
• There is no remission

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Antipsychotic treatments

• Schizophrenia has been around perhaps, since the
  beginning of humankind, however, it was not
  until the last century that it was established as
  a separate entity amongst other mental disorders.
  
• Many treatments have been devise
• Hydrotherapy
• The pouring of cold water in a stream, from a
  height of at least four feet onto the forehead,
  is one of the most certain means of subsiding
  violent, maniacal excitement that we have ever
  seen tried... wrote an anonymous physician in
  the early 1800s.

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Antipsychotic treatments

• Lobotomies (Egaz Moniz received the Nobel Prize).
• In 1940s Phenothiazenes were isolated and were
  used as pre-anesthetic medication, but quickly
  were adopted by psychiatrists to calm down their
  mental patients.
• In 1955, chlorpromazine was developed as an
  antihistaminic agent by Rhône-Pauline
  Laboratories in France. In-patients at Mental
  Hospitals dropped by 1/3.

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Antipsychotics treatment

• Antipsychotics/Neuroleptics
• Antipsychotics are the drugs currently used in
  the prevention of psychosis.
• They have also been termed neuroleptics, because
  they suppress motor activity and emotionality.
• These drugs are not a cure
• Schizophrenics must be treated with medications
  indefinitely, in as much as the disease in
  lifelong and it is preferable to prevent the
  psychotic episodes than to treat them.

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Antipsychotics/Neuroleptics

• Although the antipsychotic/neuroleptics are drugs
  used mainly in the treatment of schizophrenia,
  they are also used in the treatment of other
  psychoses associated with depression and
  manic-depressive illness, and psychosis
  associated with Alzheimers disease. These
  conditions are life-long and disabling.

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Antipsychotics/Neuroleptics

• NON-compliance is the major reason for relapse.

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Antipsychotic/Neuroleptics
OLDER DRUGS

• Three major groups
• 1) Phenothiazines
• 2) Thioxanthines
• 3) Butyrophenones

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Antipsychotics/Neuroleptics

• Old antiphsychotics /neuroleptics are D2 dopamine
  receptor antagonists. Although they are also
  effective antagonists at ACh, 5-HT, NE receptors.

dopamine receptor antagonist
D2
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Antipsychotics/Neuroleptics

• It appears that the specific interaction of
  antipsychotic drugs with D2 receptors is
  important to their therapeutic action.
• The affinities of most older classical agents
  for the D2 receptors correlate with their
  clinical potencies as antipsychotics.

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Antipsychotic/Neuroleptics

• Correlations between therapeutic potency and
  affinity for binding D2 receptors.

promazine
chlorpromazine
clozapine
thiothixene
3HHaloperidol binding IC50 (mol/L)
haloperidol
spiroperidole
Clinical dose of drug mg d-1
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Antipsychotics/Neuroleptics

• Both D1 and D2 receptors are found in high
  concentrations in the striatum and the nucleus
  accumbens.
• Clozapine has a higher affinity for the D4
  receptors than for D2.
• Recently it has been found that most
  antipsychotic drugs may also bind D3 receptors
  (therefore, they are non-selective).

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Antipsychotics/Neuroleptics

• Antipsychotics produce catalepsy (reduce motor
  activity).
• BLOCKADE OF DOPAMINE RECPTORS IN BASAL GANGLIA.
• Antipsychotics reverse hyperkinetic behaviors
  (increased locomotion and stereotyped behavior).
• BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS.
• Antipsychotics prevent the dopamine inhibition of
  prolactin release from pituitary.
• BLOCKADE OF DOPAMINE RECEPTORS IN PITUITARY.
• ? hyperprolactinemia

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Pharmacokinetics

• Absorption and Distribution

• Most antipsychotics are readily but incompletely
  absorbed.
• Significant first-pass metabolism.
• Bioavailability is 25-65.
• Most are highly lipid soluble.
• Most are highly protein bound (92-98).
• High volumes of distribution (gt7 L/Kg).
• Slow elimination.
• Duration of action longer than expected,
  metabolites are present and relapse occurs, weeks
  after discontinuation of drug.

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Pharmacokinetics

• Metabolism

• Most antipsychotics are almost completely
  metabolized.
• Most have active metabolites, although not
  important in therapeutic effect, with one
  exception. The metabolite of thioridazine,
  mesoridazine, is more potent than the parent
  compound and accounts for most of the therapeutic
  effect.

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Pharmacokinetics

• Excretion

• Antipsychotics are almost completely metabolized
  and thus, very little is eliminated unchanged.
• Elimination half-lives are 10-24 hrs.

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Antipsychotic/Neuroleptics

• Phenothiazines
• Chlorpromazine Thioridazine Fluphenazine
• Trifluopromazine Piperacetazine Perfenazine
• Mesoridazine Acetophenazine
• Carphenazine
• Prochlorperazine
• Trifluoperazine

• Aliphatic Piperidine Piperazine

Most likely to cause extrapyramidal effects.
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Antipsychotic/Neuroleptics
Piperazine
Piperidine
Aliphatic
Effect
Drug dose
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Antipsychotic/Neuroleptics

• 2) Thioxanthines
• Thiothixene
• Chlorprothixene
• Closely related to phenothiazines

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Antipsychotic/Neuroleptics

• 3) Butyrophenones
• Haloperidol
• Droperidol
• Not marketed in the USA

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Antipsychotic/Neuroleptics
Butyrophenone d.
Phenothiazine d.
Thioxanthene d.
Effect
Drug dose
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Antipsychotics/Neuroleptics

• Newer drugs have higher affinities for D1, 5-HT
  or ?-AR receptors.
• NE, GABA, Glycine and Glutamate have also been
  implicated in schizophrenia.

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Antipsychotics/Neuroleptics

• The acute effects of antipsychotics do not
  explain why their therapeutic effects are not
  evident until 4-8 weeks of treatment.
• Blockade of D2 receptors
• ?
• Short term/Compensatory effects
• Firing rate and activity of nigrostriatal and
  mesolimbic DA neurons.
• DA synthesis, DA metabolism, DA release

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Antipsychotics/Neuroleptics

• Presynaptic Effects
• Blockade of D2 receptors
• ?
• Compensatory Effects
• Firing rate and activity of nigrostriatal and
  mesolimbic DA neurons.
• DA synthesis, DA metabolism, DA release.
• Postsynaptic Effects
• Depolarization Blockade
• Inactivation of nigrostriatal and mesolimbic DA
  neurons.
• ?
• Receptor Supersensitivity

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Antipsychotic/Neuroleptics
Newer Drugs

• Pimozide
• Molindone
• Loxapine
• Clozapine
• Olanzapine
• Qetiapine
• Risperidone
• Sertindole
• Ziprasidone
• Olindone

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Antipsychotic/Neuroleptics

• Clinical Ex. Py.
• Drug Potency toxicity Sedation Hypote.

Chlorpromaz. Low Medium Medium High Haloperido
l High Very High Very High Low Thiothixene
High Medium Medium Medium Clozapine
Medium Very low Low Medium Ziprasidone
Medium Very Low Low Very low Risperidone
High Low Low Low Olanzapine High Very
Low Medium Very low Sertindole High Very
Low Very low Very Low
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Antipsychotic/Neuroleptics

• Chlorpromazine ?1 5-HT2 D2 gt D1 gt M gt ?2
• Haloperidol D2 gt D1 D4 gt ?1 gt 5-HT2 gtH1gtM ?2
  
• Clozapine D4 ?1 gt 5-HT2 M gt D2 D1 ?2
  H1
• Quetiapine 5-HT2 D2 ?1 ?2 H1
• Risperidone 5-HT2 gtgt ?1 gt H1 gt D2 gt ?2 gtgt D1
• Sertindole 5-HT2 gt D2 ?1

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Antipsychotic/Neuroleptics

• Clinical Problems with antipsychotic drugs
• include
• Failure to control negative effect
• Significant toxicity
• Parkinson-like symptoms
• Tardive Dyskinesia (10-30)
• Autonomic effects
• Endocrine effects
• Cardiac effects
• 3) Poor Concentration

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The Nigro-Striatal Pathway
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Antipsychotic/Neuroleptics

• Some antipsychotics have effects at muscarinic
  acetylcholine receptors
• dry mouth
• blurred vision
• urinary retention
• constipation
• Clozapine
• Chlorpromazine
• Thioridazine

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Antipsychotic/Neuroleptics

• Some antipsychotics have effects at a-adrenergic
  receptors
• orthostatic hypotension
• Chlorpromazine
• Thioridazine
• Some antipsychotics have effects at
  H1-histaminergic receptors
• sedation
• Risperidone
• Haloperidol

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Antipsychotic/Neuroleptics

• Blockade of D2 receptors in lactotrophs in
  breast increase prolactin concentration and may
  produce breast engorgement and galactorrhea.

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Antipsychotic/Neuroleptics

• Neuroleptic Malignant Syndrome
• Is a rare but serious side effect of neuroleptic
  (antipsychotic) therapy that can be lethal. It
  can arise at any time in the course of treatment
  and shows no predilection for age, duration of
  treatment, antipsychotic medication, or dose.

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Antipsychotic/Neuroleptics

• Neuroleptic Malignant Syndrome
• Occurs in pts. hypersensitive to the Ex.Py.
  effects of antipsychotics.
• Due to excessively rapid blockade of postsynaptic
  dopamine receptors.
• The syndrome begins with marked muscle rigidity.
• If sweating is impaired, a fever may ensue. The
  stress leukocytosis and high fever associated
  with this syndrome may be mistaken for an
  infection.
• Autonomic instability with altered blood pressure
  and heart rate is another midbrain manifestation.
• Creatine kinase isozymes are usually elevated,
  reflecting muscle damage.

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Antipsychotic/Neuroleptics

• Neuroleptic Malignant Syndrome
• Treatment
• Vigorous treatment with antiparkinsonian drugs is
  recommended as soon as possible.
• Muscle relaxants such as diazepam, dantrolene or
  bromocriptine may be helpful.

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Antipsychotic/Neuroleptics

• Drug Interactions
• Additive effects with sedatives.
• Additive effects with anticholinergics.
• Additive effects with antihistaminergics.
• Additive effects with ?-AR blocking drugs.
• Additive effects with drugs with quinidine-like
  action (thioridazine).