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SCHIZOPHRENIA- CURRENT
TRENDS IN ITS TREATMENT
CONTENTS
• Introduction
• Causes
• Symptoms
  - Positive symptoms
  - Negative symptoms
• Drug treatment
• Mechanism of action
• Adverse effects
• Current trends in the treatment
  of schizophrenia.
Schizophrenia
       • Schizophrenia is a
         complex mental
         disorder that makes it
         difficult to-
       •   Tell the differences between
           real and unreal experiences
       •   Think logically
       •   Have normal emotional
           responses
       •   Behave normally in social
           situations
CAUSES
• No one knows the exact cause of
  schizophrenia, but multiple possible
  factors have been discovered.
• It is a complex illness, possibly due to the
  dysfunction of the mesolimbic or
  mesocortical dopaminergic neurons.
• It has a strong genetic component.
SYMPTOMS
• Delusions (strongly held
    beliefs that are not based on
    reality)
• Hallucinations (Hearing or
    seeing things that are not
    there)
•   Disorganised speech
•   Disorganised behaviour
•   Irritable or tense feeling
•   Lack of emotion
POSITIVE SYMPTOMS
• Delusions
• Hallucinations
• Disorganized
  thinking
• Agitation
NEGATIVE SYMPTOMS
• Affective flattening
  (person’s range of
  emotional expression
  is clearly diminished)
• Alogia (A poverty of
  speech)
• Avolition (Inability to
  initiate and persist in
  gaol directed
  activities)
TYPES OF SCHIZOPHRENIA
• There are five types of schizophrenia:
  1.Paranoid- Person feels extremely suspicious,
    persecuted.
  2.Disorganised- person is often incoherent but
 may not have delusions.
  3.Catatonic- Person is withdrawn, mute,
 negative and often assumes very unusual
 postures.
4.Residual- person is no longer delusion or
hallucinating, but has no motivation or interest
                     in life.
 5.Undifferentiated- does not fit in one of the
above categories because the patient suffers
       from symptoms of multiple types.
DRUG TREATMENT

                           Drugs




Typical neuroleptic   Typical neuroleptic   Atypical neuroleptic
  (low potency)         (High potency)           •Aripiprazole
  •Chlorpromazine        •Fluphenazine            •Clozapine
 •Prochlopromazine        •Haloperidol           •Olanzapine
    •Thioridazine         •Thiothixene          •Resperidone
MECHANISM OF ACTION
• Dopamine receptor
  blocking activity in the
  brain.
• Serotonin receptor
  blocking activity in the
  brain.
ADVERSE EFFECTS
• COMMON SIDE EFFECTS

   -Lethargy & drowsiness

   -Anticholinergic effects          (dry mouth, blurred
 vision, constipation & retention of urine)


   -Postural Hypotension (Dizziness on standing up)
•MOVEMENT DISORDERS

  -Acute dystonia (muscle spasms)

 -Parkinsonism (tremors, stiff posture,
   immobile & expressionless face)

 -Akathisia (restless fidgeting and pacing)

-Tardive dyskinesia (repetitive involuntary
muscle movements, lip-smacking and
        protrusion of tongue)
CURRENT TRENDS IN THE
TREATMENT OF SCHIZOPHRENIA
             • Antipsychotic effects of
               novel compounds
             • Partial dopamine agonists
             • Acetylcholinesterase
               inhibitors in schizophreni
             • COX-2 inhibitors as an
               adjunctive treatment for
               schizophrenia
             • Human stem cells in the
               treatment of
               schizophrenia
ANTIPSYCHOTIC EFFECTS OF NOVEL
           COMPOUNDS
• The two new receptors which have been implicated in the
  pathophysiology of schizophrenia are 5HT2 and neurotensin-1
  receptors.
• Eplivanserine is a 5HT2 receptor antagonist. Antagonism of this
  receptor appears to regulate dopaminergic activity, and this
  compound appears to reverse amphetamine induced inhibition of
  A-10 dopaminergic cells.
• SR46349B is a neurotensin-1 receptor antagonist that appears to
  diminish the spontaneous activity of dopaminergic neurons.
• Both these drugs were effective in treating the negative and
  depressive symptoms as well.
PARTIAL DOPAMINE AGONISTS
• The dopaminergic hypothesis of schizophrenia indicates that in this
  condition there is a both hyperdopaminergic state in the cortical
  mesolimbic tract (causing positive symptoms) and a
  hypodopaminergic state in the mesocortical tract (causing negative
  symptoms).
• The full agonist allows full neurotransmitter activity at the synaptic
  site .
• An antagonist, when bound to the receptor allows no receptor
  activity. In contrast, a partial agonist will allow some
  neurotransmitter activity when bound to the receptor.
• Ariprazole is a dopamine partial agonist that has recently been
  approved in the United States. It is 10 times more potent than other
  drugs.
ACETYLCHOLINESTERASE
    INHIBITORS IN SCHIZOPHRENIA
• Neurotransmitters implicated in the pathogenesis of schizophrenia
  have included dopamine, serotonin, glutamine and acetylcholine.
• Cognitive impairment in schizophrenia may at least partially due to
  diminished acetylcholine activity in the cortex.
• Donepezil is an acetylcholinesterase inhibitor that appears to
  enhance cognitive functioning in patients with schizophrenia.
COX-2 INHIBITORS AS AN ADJUNCTIVE
  TREATMENT FOR SCHIZOPHRENIA
• Recently, increased attention has been paid to the interface
  between the immune system and the treatment of schizophrenia.
• When the mentally ill group was afflicted with an infection, half
  showed improvements in their psychotic symptoms.
• It is believed that there may be an imbalance between the type1 and
  type2 immune systems in patients with psychosis.
• Schizophrenic patients who are treatment-resistant appear to have
  an increase in interleukin-6 level, which is a part of type1 system.
• COX-2 inhibitor Celecoxib is an inhibitor of prostaglandin E2 and
  IL-6 which was found to restore the imbalance between the type1
  and type2 immune systems.
HUMAN STEM CELLS IN THE
      TREATMENT OF SCHIZOPHRENIA
• The National Institutes of Health states that stem cell “have the
  remarkable potential to develop into many different cells types in the
  body during early life and growth”.
• The stem cells can be coaxed to become brain cells such as
  neurons. Because they have the DISC1 mutation, they stand to play
  an important role in the screening of drugs for treatments of major
  mental illnesses such as schizophrenia.
• Inspite of holding the key to an effective treatment, the stem cell
  research may not work for the disorder as they are still not exactly
  sure what goes wrong in the schizophrenic brain.
REFERENCES
•   Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-
    generation versus first-generation antipsychotic drugs for
    schizophrenia: a meta-analysis. Lancet. 2009;373:31-41. Epub
    2008 Dec 6. [PubMed]
•   Psych Central, National Mental Health Association,
    National Institute for Mental Health, National Alliance for the
    Mentally Ill, Internet Mental Health.
•   Kostic D, Manos G, Stock E, et al. Long-term effects of
    aripiprazole on the negative symptoms of schizophrenia. J Eur
    Coll Neuropsychopharmacol. 2003;13(supp 4):S328.
•   Marder SR, McQuade RD, Stock E, et al. Aripiprazole in the
    treatment of schizophrenia: safety and tolerability in short-term,
    placebo-controlled trials. Schizophr Res. 2003;61:123-126.
Schizophrenia

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Schizophrenia

  • 2. CONTENTS • Introduction • Causes • Symptoms - Positive symptoms - Negative symptoms • Drug treatment • Mechanism of action • Adverse effects • Current trends in the treatment of schizophrenia.
  • 3. Schizophrenia • Schizophrenia is a complex mental disorder that makes it difficult to- • Tell the differences between real and unreal experiences • Think logically • Have normal emotional responses • Behave normally in social situations
  • 4. CAUSES • No one knows the exact cause of schizophrenia, but multiple possible factors have been discovered. • It is a complex illness, possibly due to the dysfunction of the mesolimbic or mesocortical dopaminergic neurons. • It has a strong genetic component.
  • 5.
  • 6. SYMPTOMS • Delusions (strongly held beliefs that are not based on reality) • Hallucinations (Hearing or seeing things that are not there) • Disorganised speech • Disorganised behaviour • Irritable or tense feeling • Lack of emotion
  • 7. POSITIVE SYMPTOMS • Delusions • Hallucinations • Disorganized thinking • Agitation
  • 8. NEGATIVE SYMPTOMS • Affective flattening (person’s range of emotional expression is clearly diminished) • Alogia (A poverty of speech) • Avolition (Inability to initiate and persist in gaol directed activities)
  • 9. TYPES OF SCHIZOPHRENIA • There are five types of schizophrenia: 1.Paranoid- Person feels extremely suspicious, persecuted. 2.Disorganised- person is often incoherent but may not have delusions. 3.Catatonic- Person is withdrawn, mute, negative and often assumes very unusual postures.
  • 10. 4.Residual- person is no longer delusion or hallucinating, but has no motivation or interest in life. 5.Undifferentiated- does not fit in one of the above categories because the patient suffers from symptoms of multiple types.
  • 11. DRUG TREATMENT Drugs Typical neuroleptic Typical neuroleptic Atypical neuroleptic (low potency) (High potency) •Aripiprazole •Chlorpromazine •Fluphenazine •Clozapine •Prochlopromazine •Haloperidol •Olanzapine •Thioridazine •Thiothixene •Resperidone
  • 12. MECHANISM OF ACTION • Dopamine receptor blocking activity in the brain. • Serotonin receptor blocking activity in the brain.
  • 13. ADVERSE EFFECTS • COMMON SIDE EFFECTS -Lethargy & drowsiness -Anticholinergic effects (dry mouth, blurred vision, constipation & retention of urine) -Postural Hypotension (Dizziness on standing up)
  • 14. •MOVEMENT DISORDERS -Acute dystonia (muscle spasms) -Parkinsonism (tremors, stiff posture, immobile & expressionless face) -Akathisia (restless fidgeting and pacing) -Tardive dyskinesia (repetitive involuntary muscle movements, lip-smacking and protrusion of tongue)
  • 15. CURRENT TRENDS IN THE TREATMENT OF SCHIZOPHRENIA • Antipsychotic effects of novel compounds • Partial dopamine agonists • Acetylcholinesterase inhibitors in schizophreni • COX-2 inhibitors as an adjunctive treatment for schizophrenia • Human stem cells in the treatment of schizophrenia
  • 16. ANTIPSYCHOTIC EFFECTS OF NOVEL COMPOUNDS • The two new receptors which have been implicated in the pathophysiology of schizophrenia are 5HT2 and neurotensin-1 receptors. • Eplivanserine is a 5HT2 receptor antagonist. Antagonism of this receptor appears to regulate dopaminergic activity, and this compound appears to reverse amphetamine induced inhibition of A-10 dopaminergic cells. • SR46349B is a neurotensin-1 receptor antagonist that appears to diminish the spontaneous activity of dopaminergic neurons. • Both these drugs were effective in treating the negative and depressive symptoms as well.
  • 17. PARTIAL DOPAMINE AGONISTS • The dopaminergic hypothesis of schizophrenia indicates that in this condition there is a both hyperdopaminergic state in the cortical mesolimbic tract (causing positive symptoms) and a hypodopaminergic state in the mesocortical tract (causing negative symptoms). • The full agonist allows full neurotransmitter activity at the synaptic site . • An antagonist, when bound to the receptor allows no receptor activity. In contrast, a partial agonist will allow some neurotransmitter activity when bound to the receptor. • Ariprazole is a dopamine partial agonist that has recently been approved in the United States. It is 10 times more potent than other drugs.
  • 18. ACETYLCHOLINESTERASE INHIBITORS IN SCHIZOPHRENIA • Neurotransmitters implicated in the pathogenesis of schizophrenia have included dopamine, serotonin, glutamine and acetylcholine. • Cognitive impairment in schizophrenia may at least partially due to diminished acetylcholine activity in the cortex. • Donepezil is an acetylcholinesterase inhibitor that appears to enhance cognitive functioning in patients with schizophrenia.
  • 19. COX-2 INHIBITORS AS AN ADJUNCTIVE TREATMENT FOR SCHIZOPHRENIA • Recently, increased attention has been paid to the interface between the immune system and the treatment of schizophrenia. • When the mentally ill group was afflicted with an infection, half showed improvements in their psychotic symptoms. • It is believed that there may be an imbalance between the type1 and type2 immune systems in patients with psychosis. • Schizophrenic patients who are treatment-resistant appear to have an increase in interleukin-6 level, which is a part of type1 system. • COX-2 inhibitor Celecoxib is an inhibitor of prostaglandin E2 and IL-6 which was found to restore the imbalance between the type1 and type2 immune systems.
  • 20. HUMAN STEM CELLS IN THE TREATMENT OF SCHIZOPHRENIA • The National Institutes of Health states that stem cell “have the remarkable potential to develop into many different cells types in the body during early life and growth”. • The stem cells can be coaxed to become brain cells such as neurons. Because they have the DISC1 mutation, they stand to play an important role in the screening of drugs for treatments of major mental illnesses such as schizophrenia. • Inspite of holding the key to an effective treatment, the stem cell research may not work for the disorder as they are still not exactly sure what goes wrong in the schizophrenic brain.
  • 21. REFERENCES • Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second- generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373:31-41. Epub 2008 Dec 6. [PubMed] • Psych Central, National Mental Health Association, National Institute for Mental Health, National Alliance for the Mentally Ill, Internet Mental Health. • Kostic D, Manos G, Stock E, et al. Long-term effects of aripiprazole on the negative symptoms of schizophrenia. J Eur Coll Neuropsychopharmacol. 2003;13(supp 4):S328. • Marder SR, McQuade RD, Stock E, et al. Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials. Schizophr Res. 2003;61:123-126.