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DR. SUBRATA NASKAR
MD Psychiatry Trainee
Email: nsubrata09@gmail.com
Please download the presentation for availability of ...
PLAN OF PRESENTATION
• WHAT IS PSYCHOSIS ?
• DIFFERENCE BETWEEN PSYCHOSIS AND NEUROSIS
• SYMPTOMS IN PSYCHOSIS
• NEUROBIOL...
WHAT IS PSYCHOSIS ?
• MENTAL DISORDER IN WHICH
• THE THOUGHTS
• AFFECTIVE RESPONSE
• ABILITY TO RECOGNIZE REALITY
• ABILIT...
• PSYCHOSIS (FROM THE GREEK ΨΥΧΉ PSYCHE,
"MIND/SOUL", AND -ΩΣΙΣ -OSIS, "A NORMAL
CONDITION OR DERANGEMENT")
• THER TERM WA...
PSYCHOSIS
• INSIGHT IS ABSENT
• JUDGEMENT & REASONING IS
IMPAIRED
• REALITY CONTACT IS LOST
• DELUSIONS USUALLY PRESENT
• ...
• PSYCHOSIS MAY BE
• PRIMARY
• SECONDARY
• CAUSES OF PRIMARY PSYCHOSIS
• PSYCHOSES ORIGINATING FROM PSYCHIATRIC ILLNESS
• ...
SYMPTOMS IN PSYCHOSIS
• POSITIVE SYMPTOMS ARE OFTEN THE MOST EMPHASIZED
SYMPTOMS AS THEY ARE
• DRAMATIC, CAN ERUPT SUDDENL...
SYMPTOMS IN PSYCHOSIS
• AFFECTIVE SYMPTOMS
• DEPRESSED MOOD
• ANXIOUS MOOD
• GUILT
• TENSION
• IRRITABILITY
• WORRY
• AGGR...
SYMPTOMS IN PSYCHOSIS
• COGNITIVE SYMPTOMS
• PROBLEMS REPRESENTING AND MAINTAINING GOALS
• PROBLEMS ALLOCATING ATTENTIONAL...
POSITIVE SYMPTOMS
• DELUSIONS
• HALLUCINATIONS
• DISTORTIONS OR EXAGGERATIONS IN LANGUAGE AND COMMUNICATION
• DISORGANIZED...
ITEMS IN THE SCALE FOR THE POSITIVE SYNDROME
(SAPS)
• HALLUCINATIONS
• AUDITORY HALLUCINATIONS
• VOICES COMMENTING
• VOICE...
ITEMS IN THE SCALE FOR THE POSITIVE SYNDROME
(SAPS)
• BIZARRE BEHAVIOR
• CLOTHING AND BEHAVIOR
• SOCIAL AND SEXUAL BEHAVIO...
NEGATIVE SYMPTOMS
• ALOGIA
• DYSFUNCTION OF COMMUNICATION; RESTRICTIONS IN THE FLUENCY AND
PRODUCTIVITY OF THOUGHT AND SPE...
ITEMS IN THE SCALE FOR ASSESSMENT OF NEGATIVE SYMPTOMS
(SANS)
• AFFECTIVE FLATTENING OR
BLUNTING
• UNCHANGING FACIAL
EXPRE...
ITEMS IN THE SCALE FOR ASSESSMENT OF NEGATIVE SYMPTOMS
(SANS)
• AVOLITION—APATHY
• GROOMING AND HYGIENE
• IMPERSISTENCE AT...
NEUROBIOLOGY OF PSYCHOSIS
• THERE ARE VARIOUS THEORIES REGARDING THE PATHWAYS
INVOLVED IN THE DEVELOPMENT OF PSYCHOSIS
2 M...
THE DOPAMINERGIC PATHWAYS
• THERE ARE 4 WELL DEFIENED AND A RECENTLY DISCOVERED 5TH
DOPAMINERGIC PATHWAYS NAMELY
• MESOLIM...
DOPAMINE
RECEPTORS
There are at least
five subtypes of
receptors:
Receptor
• D1
• D2
• D3
• D4
• D5
DOPAMINE SYNAPSE
DA
L-...
THE MESOLIMBIC PATHWAY
• ORIGIN:
• DOPAMINERGIC CELL BODIES IN THE VENTRAL TEGMENTAL AREA OF THE
BRAINSTEM
• PROJECTS TO:
...
MESOLIMBIC PATHWAY
• RESPONSIBLE FOR:
• IN NORMAL PERSON
• EMOTIONAL BEHAVIOUR
• MOTIVATION
• PLEASURE
• REWARD
• IN PSYCHOSIS:
• POSITIVE SY...
• IT IS BELIEVED THAT IT IS HYPERACTIVITY SPECIFICALLY IN THIS PARTICULAR
DOPAMINE PATHWAY THAT MEDIATES THE POSITIVE SYMP...
THE MESOCORTICAL PATHWAY
• ORIGIN:
• DOPAMINERGIC CELL BODIES OF THE VENTRAL TEGMENTAL AREA
PROJECTS TO:
• DORSOLATERAL PREFRONTAL CORTEX PATHWAY:
• IN NORMAL PERSON
• REGULATES COGNITION AND EXECUTIVE FUNCTION
• IN PSYCHOSIS –...
MESOCORTICAL PATHWAY
HYPODOPAMINERGIC
DLPFC
OFC
NIGROSTRIATAL DOPAMINERGIC PATHWAY
• ORIGIN:
• CELL BODIES IN THE PARS COMPACTA OF THE SUBSTANTIA NIAGRA
• PROJECTS TO
• S...
HYPERACTIVITY/ HYPOACTIVITY
• DOPAMINE DEFICIENCY IN BASAL GANGLIA:
• AKATHISIA
• DYSTONIA
• DOPAMINE HYPERACTIVITY IN BASAL GANGLIA
• HYPERKINETIC MO...
• THIS MOVEMENT DISORDER CAUSES FACIAL AND TONGUE MOVEMENTS, SUCH
AS CONSTANT CHEWING, TONGUE PROTRUSIONS, FACIAL GRIMACIN...
TUBULOINFUNDIBULAR PATHWAY
• ORIGIN
• HYPOTHALAMUS
• PROJECTS TO
• ANTERIOR PITUTARY
• NORMALLY THESE NEURONES ARE ACTIVE AND THEY INHIBIT PROLACTIN
RELEASE
IN POSTPARTUM
STATE, ACTIVITY
DECREASES
PROLACTIN
...
THE THALAMIC PATHWAY
• ORIGIN
• ARISES FROM MULTIPLE SITES, INCLUDING THE
• PERIAQUEDUCTAL GRAY
• VENTRAL MESENCEPHALON
• ...
• FUNCTION
• ITS FUNCTION IS NOT CURRENTLY WELL KNOWN
• MAY BE INVOLVED IN SLEEP AND AROUSAL MECHANISMS
GLUMATE PATHWAYS
• THERE ARE 5 GLUTAMATE PATHWAYS
• CORTICOBRAINSTEM GLUTAMATE PATHWAY
• CORTICOSTRIATAL GLUTAMATE PATHWAY...
CORTICOBRAINSTEM GLUTAMATE PATHWAY
• ORIGIN:
• CORTICAL PYRAMIDAL NEURONES, MOSTLY IN LAMINA 5
• PROJECTS TO
• BRAINSTEM N...
CORTICOBRAINSTEM GLUTAMATE PATHWAY
CORTICAL PYRAMIDAL NEURONES, MOSTLY IN LAMINA 5
BRAINSTEM NEUROTRANSMITTER CENTRES
ACTION
• ACTS AS A BRAKE ON THE MESOLIMBIC DOPAMINE PATHWAY (MLDP)
HOW ?
• IT CONNECTS THE MLDP WITH AN INHIBITORY GABA IN...
ANOTHER HYPOTHESIS
• A MAJOR CURRENT HYPOTHESIS FOR SCHIZOPHRENIA INVOLVES NMDA
RECEPTORS IN THIS PATHWAY.
• THE NMDA RECE...
WHAT IS THE HYPOTHESIS ?
NMDA RECEPTORS SPECIFICALLY IN THE CORTICOBRAINSTEM GLUTAMATE
PROJECTION MIGHT BE HYPOACTIVE IN U...
• IT HAS BEEN SEEN THAT PCP ALSO MIMICS THE COGNITIVE, NEGATIVE
AND AFFECTIVE SYMPTOMS
• THESE ADDITIONAL CLINICAL OBSERVA...
NORMALLY, THE DESCENDING CORTICOBRAINSTEM
GLUTAMATE NEURONS ACT AS ACCELERATORS TO
MESOCORTICAL DOPAMINE NEURONS
CORTICOBR...
CORTICOSTRIATAL GLUTAMATE PATHWAY
• ORIGIN
• PYRAMIDAL NEURONES OF CORTEX (LAMINA 5)
• PROJECTS TO:
STRIATUM THALAMUS
IF P...
• NORMALLY, THIS CORTICOSTRIATAL GLUTAMATE PROJECTION TO THE
STRIATUM TERMINATES ON GABA NEURONS IN THE STRIATUM
• THESE G...
PYRAMIDAL GLUTAMINERGIC NEURONS DESCEND
FROM THE PREFRONTAL CORTEX TO THE STRIATUM,
WHERE THEY TERMINATE ON GABA NEURONS
G...
THALAMOCORTICAL GLUTAMATE PATHWAY
• ORIGIN:
• THALAMUS
• INNERVATES:
• PYRAMIDAL NEURONES IN CORTEX
• IT IS ACTUALLY THE R...
NMDA RECEPTOR HYPOFUNCTION
+
INCREASED MESOLIMBIC DOPAMINE DRIVE
FAILURE OF THALAMIC FILTERS
EXCESS INFORMATION ESCAPES TO...
DOPAMINERGIC INPUT TO THE NUCLEUS ACCUMBENS
VIA THE MESOLIMBIC DOPAMINE PATHWAY
INHIBITORY EFFECT ON GABA NEURONS
REDUCED ...
CORTICOTHALAMIC GLUTAMATE PATHWAY
• ORIGIN
• LAMINA 6 IN CORTEX
• PROJECTS
• THALAMUS
CORTICOCORTICAL GLUTAMATE PATHWAY
• ORIGIN
• CORTICAL PYRAMIDAL NEURONES
• PROJECTS
• CORTICAL PYRAMIDAL NEURONES
• CORTIC...
ROLE OF ANTIPSYCHOTICS
• THE MAIN MECHANISM OF ACTION OF ANY ANTIPSYCHOTIC IS
BLOCKADE OF DOPAMINE RECEPTORS.
• ANTIPSYCHO...
• TYPICAL ANTIPSYCHOTICS
• PHENOTHIAZINES (CHLORPROMAZINE, PERPHENAZINE, FLUPHENAZINE,
THIORIDAZINE ET AL)
• THIOXANTHENES...
WHAT MAKES AN ANTIPSYCHOTIC TYPICAL ?
• D2 RECEPTOR ANTAGONISM.
• MUSCARINIC CHOLINERGIC BLOCKING PROPERTIES
• WHAT DOES D2 RECEPTOR ANTAGONISM DO ?
• CONVENTIONAL ANTIPSYCHOTICS SEEK OUT AND BLOCK ALMOST EVERY
D2 RECEPTOR IN BRAIN...
• NIGROSTRIATAL PATHWAY
• DYSTONIA
• AKATHISIA
• DRUG INDUCED PARKINSONISM
• TARDIVE DYSKINESIA
• TUBULOINFUNDIBULAR PATHW...
HOW MUSCARINIC CHOLINERGIC RECEPTOR ACTIVATION
CAUSES EXTRAPYRAMIDAL SYMPTOMS ?
• DOPAMINE AND ACETYLCHOLINE HAS RECIPROCA...
ANTIPSYCHOTIC
USED
D2 BLOCKADE
DECREASED
DOPAMINE
DECREASED
BLOCKING OF
CHOLINERGIC
NEURONES
INCREASED
ACETYLCHOLINE
EXTRA...
SO,
• MORE DOPAMINE = LESS ACETYLCHOLINE
• LESS DOPAMINE = MORE ACETYLCHOLINE
• LESS ACETYLCHOLINE = LESS EPS
• MORE ACETY...
MORE ACETYLCHOLINE RELEASE
DOPAMINE
NEURONE
CHOLINERGIC
NEURONE
DOPAMINE
NEURONE
CHOLINERGIC
NEURONE
ATYPICAL ANTIPSYCHOTI...
• HENCE,
• TYPICAL ANTIPSYCHOTICS HAVE MORE EXTRAPYRAMIDAL SIDEEFFECTS THAN ATYPICAL
ANTIPSYCHOTICS
• ONE COMPENSATION FOR...
THIS CAN CAUSE UNDESIRABLE SIDE EFFECTS SUCH AS DRY MOUTH,
BLURRED VISION, CONSTIPATION, AND COGNITIVE BLUNTING
DIFFERING ...
• ANTIPSYCHOTICS MAY HAVE H1 RECEPTOR BLOCKING PROPERTY
• WEIGHT GAIN
• DROWSINESS
• MAY HAVE α1 ANTIADRENERGIC PROPERTIES
• DROWSINESS
• ORTHOSTATIC HYPOTENSION
NEUROLEPTIC MALIGNANT SYNDROME
• IS A RARE BUT SERIOUS SIDE EFFECT OF NEUROLEPTIC
(ANTIPSYCHOTIC) THERAPY THAT CAN BE LETH...
NEUROLEPTIC MALIGNANT SYNDROME
• OCCURS IN PTS. HYPERSENSITIVE TO THE EX.PY. EFFECTS OF
ANTIPSYCHOTICS.
• DUE TO EXCESSIVE...
• TREATMENT
• VIGOROUS TREATMENT WITH ANTIPARKINSONIAN DRUGS IS RECOMMENDED
AS SOON AS POSSIBLE.
• MUSCLE RELAXANTS SUCH A...
TYPICAL ANTIPSYCHOTICS
WHAT MAKES ANTIPSYCHOTICS ATYPICAL ?
• LOW EPS
• GOOD FOR NEGATIVE SYMPTOMS
• THEY USUALLY HAVE 4 TYPES OF ACTIONS:
• SERO...
SEROTONIN RECEPTORS
• PRESYNAPTIC - 5HT1A AND 5HT1B/1D
• POSTSYNAPTIC – 5HT1A, 5HT1B/1D, 5HT2A, 5HT2C, 5HT3, 5HT4,
5HT5, 5...
5HT1A INHIBITS CORTICAL PYRAMIDAL
NEURONE
REGULATES HORMONES, COGNITION,
ANXIETY, DEPRESSION
5HT2A EXCITES CORTICAL PYRAMI...
• 5HT1A AND 5HT2A HAVE OPPOSITE ACTION IN REGULATING DOPAMINE
RELEASE.
5HT1A
SOMATODENDRITIC
AUTORECEPTORS
5HT1B/1D
5HT1B/...
• MANY ANTIPSYCHOTICS ARE ANTAGONISTS AT THE 5HT2A RECEPTOR AS
WELL AS THE D2 RECEPTORS.
• THIS ANTAGONISTIC ACTION MAY BE...
DA NEURONE
DA NEURONE OF
NIGROSTRIATAL TRACT
5HT NEURONE
CAPSULE
SDA MOLECULES
RELEASED
SDA BINDS AT THE 5HT2A RECEPTORS
B...
5HT2A ANTAGONISM REDUCES NEGATIVE SYMPTOMS
• SOME EXPERTS BELIEVE THAT ATYPICAL ANTIPSYCHOTICS DO NOT REALLY
REDUCE NEGATI...
5HT2A ANTAGONISM MAY IMPROVE POSITIVE
SYMPTOMS
• 5HT1A AND 5HT2A RECEPTORS ALONG WITH DOPAMINE HAS EFFECT
ON GLUTAMATE REL...
• IT IS POSSIBLE THAT STIMULATORY EFFECT OF 5HT2A RECEPTORS ON
GLUTAMATE RELEASE MAY BE LINKED TO CAUSATION OF
HALLUCINATI...
ACTIVATED BY 5HT
RELEASE OF
GLUTAMATE
SEROTONIN
5HT2A
5HT1A
5HT2A INHIBITOR
ACTIVATED BY 5HT
INHIBITION OF
GLUTAMATE RELEA...
• ITS HAS BEEN FOUND THERE IS ABNORMAL ACTIVATION OF 5HT2A
RECEPTORS ON CORTICAL GLUTAMATE NEURONES IN HALLUCINOGEN
ABUSE ...
• IDEAL GOAL:
• 70 – 80% BLOCKADE OF D2 RECEPTORS IN MESOLIMBIC PATHWAY
• COMPLETE BLOCKADE OF MESOCORTICAL 5HT2A RECEPTOR...
ROLE OF 5HT2A ANTAGONISTS IN HYPERPROLACTINEMIA
• DOPAMINE INHIBITS PROLACTIN RELEASE BY STIMULATING D2
RECEPTORS
DOPAMINE...
• SEROTONIN PROMOTES PROLACTIN RELEASE BY STIMULATING 5HT2A
RECEPTORS
SEROTONIN (5HT) STIMULATES PROLACTIN RELEASE FROM PI...
CONVENTIONAL ANTIPSYCHOTICS AND PROLACTIN
• CONVENTIONAL ANTIPSYCHOTIC DRUGS ARE D2 ANTAGONISTS
• THUS OPPOSE DOPAMINE'S I...
ATYPICAL ANTIPSYCHOTICS AND PROLACTIN.
• SEROTONIN 5HT2A ANTAGONISM REVERSES THE ABILITY OF D2 ANTAGONISM TO INCREASE PROL...
D2 ANTAGONISM WITH RAPID DISSOCIATION
• AN ANTIPSYCHOTIC IS ATYPICAL BY ITS PROPERTY OF RAPID
DISSOCIATION FROM D2 RECEPTO...
• BECAUSE OF THEIR BIOCHEMICAL NATURE, THE
BINDING OF ATYPICAL ANTIPSYCHOTICS TO
POSTSYNAPTIC D2 RECEPTORS IS LOOSE, THAT ...
D2 PARTIAL AGONISM (DPA) MAKES AN ANTIPSYCHOTIC ATYPICAL
• A NEW CLASS OF ANTIPSYCHOTICS IS EMERGING THAT STABILIZES
DOPAM...
• INSTEAD, A PARTIAL AGONIST BINDS IN AN INTERMEDIARY MANNER,
WITH ANTIPSYCHOTIC ACTIONS BUT NO EPS.
• FOR THIS REASON, PA...
5HT1A PARTIAL AGONIST (SPA) ACTIONS MAKE AN ANTIPSYCHOTIC ATYPICAL
• AGONIST ACTIONS AT 5HT1A RECEPTORS
• INCREASE IN DOPA...
• REDUCED GLUTAMATE RELEASE BY SPA - IN PREFRONTAL CORTEX COULD
THEORETICALLY REDUCE POSITIVE SYMPTOMS.
• THUS, 5HT1A AGON...
ATYPICAL ANTIPSYCHOTICS IN CLINICAL
PRACTICE
• ZYPREXA (OLANZAPINE)
• SEROQUEL (QUETIAPINE)
• GEODON (ZIPRASIDONE)
• FANAP...
GLUTAMATE AGONISTS OR ANTAGONISTS FOR
TREATMENT OF PSYCHOSIS
NMDA ANTAGONISTS
• EXCESSIVE GLUTAMATE ACTIVITY COULD LEAD TO...
• BLOCKING EXCESSIVE AND EXCITOTOXIC GLUTAMATE NEUROTRANSMISSION WITH
NMDA ANTAGONISTS MIGHT PREVENT DAMAGE OR DEATH TO NE...
AMPAKINES
• AMPA (Α-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLE-PROPIONIC ACID) RECEPTORS ARE
ONE OF THE GLUTAMATE RECEPTOR SUBTY...
mGluR PRESYNAPTIC ANTAGONISTS/POSTSYNAPTIC
AGONISTS
• ANOTHER CLASS OF GLUTAMATE RECEPTOR, KNOWN AS METABOTROPIC
GLUTAMATE...
GLYCINE AGONIST
AGONISTS AT THE GLYCINE SITE OF NMDA RCEPTORS INCLUDE THE
NATURALLY OCCURRING AMINO ACIDS GLYCINE AND D-SE...
GLYT1 INHIBITORS
• GLYCINE TRANSPORTERS ON GLIAL CELLS, KNOWN AS GLYT1, HAS ROLE IN
TERMINATING THE ACTION OF GLYCINE RELE...
GLYT1 INHIBITORS
THE GLYCINE TRANSPORTER 1 (GLYT1) NORMALLY TERMINATES
THE ACTIONS OF GLYCINE AT NMDA RECEPTORS IN THE
GLU...
SUMMARY
• MENTAL DISORDER IN WHICH THE THOUGHTS, AFFECTIVE RESPONSE,
ABILITY TO RECOGNIZE REALITY, ABILITY TO COMMUNICATE ...
• ANTIPSYCHOTICS ARE BROADLY DIVIDED IN TYPICAL AND ATYPICAL
ANTIPSYCHOTICS.
• AN ANTIPSYCHOTIC IS CONSIDERED TYPICAL DEPE...
• THERE ARE OTHER ANTIPSYCHOTICS IN THE PROCESS OF RESEARCH
WHICH INCLUDES
• NMDA ANTAGONISTS
• AMPAKINES
• mGluR PRESYNAP...
BIBLIOGRAPHY
• COMPREHENSIVE TEXTBOOK OF PSYCHIATRY, VOL 2, KAPLAN AND
SADOCK.
• SYNOPSIS OF PSYCHIATRY, 10TH EDITION - BE...
THANK YOU
THE NEUROBIOLOGY OF PSYCHOSIS AND THE ROLE OF ANTIPSYCHOTICS
THE NEUROBIOLOGY OF PSYCHOSIS AND THE ROLE OF ANTIPSYCHOTICS
THE NEUROBIOLOGY OF PSYCHOSIS AND THE ROLE OF ANTIPSYCHOTICS
THE NEUROBIOLOGY OF PSYCHOSIS AND THE ROLE OF ANTIPSYCHOTICS
THE NEUROBIOLOGY OF PSYCHOSIS AND THE ROLE OF ANTIPSYCHOTICS
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THE NEUROBIOLOGY OF PSYCHOSIS AND THE ROLE OF ANTIPSYCHOTICS

  1. 1. DR. SUBRATA NASKAR MD Psychiatry Trainee Email: nsubrata09@gmail.com Please download the presentation for availability of animation employed.
  2. 2. PLAN OF PRESENTATION • WHAT IS PSYCHOSIS ? • DIFFERENCE BETWEEN PSYCHOSIS AND NEUROSIS • SYMPTOMS IN PSYCHOSIS • NEUROBIOLOGY • DOPAMINE HYPOTHESIS • GLUTAMATE HYPOTHESIS • ROLE OF ANTIPSYCHOTICS • DISCUSSION ABOUT TYPICALITY AND ATYPICALITY OF ANTIPSYCHOTICS • VARIOUS TYPES OF ANTIPSYCHOTIC MECHANISM OF ACTION • NEWER CONCEPTS TO CONTROL PSYCHOSIS PHARMACOLOGICALLY • BIBLIOGRAPHY
  3. 3. WHAT IS PSYCHOSIS ? • MENTAL DISORDER IN WHICH • THE THOUGHTS • AFFECTIVE RESPONSE • ABILITY TO RECOGNIZE REALITY • ABILITY TO COMMUNICATE AND RELATE TO OTHERS • ARE SUFFICIENTLY IMPAIRED TO INTERFERE GROSSLY WITH THE CAPACITY TO DEAL WITH REALITY IS CALLED PSYCHOSIS. • THE CLASSIC CHARACTERISTICS OF PSYCHOSIS ARE • IMPAIRED REALITY TESTING • HALLUCINATIONS • DELUSIONS • ILLUSIONS
  4. 4. • PSYCHOSIS (FROM THE GREEK ΨΥΧΉ PSYCHE, "MIND/SOUL", AND -ΩΣΙΣ -OSIS, "A NORMAL CONDITION OR DERANGEMENT") • THER TERM WAS FIRST USED BY ERNST VON FEUCHTERSLEBEN
  5. 5. PSYCHOSIS • INSIGHT IS ABSENT • JUDGEMENT & REASONING IS IMPAIRED • REALITY CONTACT IS LOST • DELUSIONS USUALLY PRESENT • TRUE HALLUCINATIONS USUALLY PRESENT • CHANGE IN PERSONALITY MAY BE THERE NEUROSIS • INSIGHT IS PRESENT • JUDGEMENT & REASONING IS INTACT • REALITY CONTACT IS PRESENT • DELUSIONS ARE ABSENT • TRUE HALLUCINATIONS ARE USUALLY ABSENT • CHANGE IN PERSONALITY IS USUALLY ABSENT.
  6. 6. • PSYCHOSIS MAY BE • PRIMARY • SECONDARY • CAUSES OF PRIMARY PSYCHOSIS • PSYCHOSES ORIGINATING FROM PSYCHIATRIC ILLNESS • SCHIZOPHRENIA • SOME CASES OF MAJOR DEPRESSION • BIPOLAR DISORDER • SCHIZOAFFECTIVE DISORDER • DELUSIONAL DISORDER • BRIEF PSYCHOTIC DISORDER • SHARED PSYCHOTIC DISORDER • CAUSES OF SECONDARY PSYCHOSIS • MEDICAL CONDITIONS • SUBSTANCE INTOXICATION OR WITHDRAWAL • FOCAL BRAIN LESIONS
  7. 7. SYMPTOMS IN PSYCHOSIS • POSITIVE SYMPTOMS ARE OFTEN THE MOST EMPHASIZED SYMPTOMS AS THEY ARE • DRAMATIC, CAN ERUPT SUDDENLY WHEN A PATIENT DECOMPENSATES INTO A PSYCHOTIC EPISODE (OFTEN CALLED A PSYCHOTIC "BREAK," AS IN BREAK FROM REALITY), AND • ARE THE SYMPTOMS MOST EFFECTIVELY TREATED BY ANTIPSYCHOTIC MEDICATIONS. • NEGATIVE SYMPTOMS “REPRESENT A LOSS OR DIMINUTION OF NORMAL FUNCTIONS”
  8. 8. SYMPTOMS IN PSYCHOSIS • AFFECTIVE SYMPTOMS • DEPRESSED MOOD • ANXIOUS MOOD • GUILT • TENSION • IRRITABILITY • WORRY • AGGRESSIVE & IMPULSIVE SYMPTOMS • OVERT HOSTILITY, SUCH AS VERBAL OR PHYSICAL ABUSIVENESS OR EVEN ASSAULT • SELF-INJURIOUS BEHAVIORS INCLUDING SUICIDE • ARSON OR OTHER PROPERTY DAMAGE • SEXUAL ACTING OUT
  9. 9. SYMPTOMS IN PSYCHOSIS • COGNITIVE SYMPTOMS • PROBLEMS REPRESENTING AND MAINTAINING GOALS • PROBLEMS ALLOCATING ATTENTIONAL RESOURCES • PROBLEMS FOCUSING ATTENTION • PROBLEMS SUSTAINING ATTENTION • PROBLEMS EVALUATING FUNCTIONS • PROBLEMS MONITORING PERFORMANCE • PROBLEMS PRIORITIZING • PROBLEMS MODULATING BEHAVIOR BASED UPON SOCIAL CUES • PROBLEMS WITH SERIAL LEARNING • IMPAIRED VERBAL FLUENCY • DIFFICULTY WITH PROBLEM SOLVING
  10. 10. POSITIVE SYMPTOMS • DELUSIONS • HALLUCINATIONS • DISTORTIONS OR EXAGGERATIONS IN LANGUAGE AND COMMUNICATION • DISORGANIZED SPEECH • DISORGANIZED BEHAVIOR • CATATONIC BEHAVIOR • AGITATION *STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY
  11. 11. ITEMS IN THE SCALE FOR THE POSITIVE SYNDROME (SAPS) • HALLUCINATIONS • AUDITORY HALLUCINATIONS • VOICES COMMENTING • VOICES CONVERSING • SOMATIC OR TACTILE HALLUCINATIONS • OLFACTORY HALLUCINATIONS • VISUAL HALLUCINATIONS • DELUSIONS • PERSECUTORY DELUSIONS • DELUSIONS OF JEALOUSY • DELUSIONS OF GUILT OR SIN • GRANDIOSE DELUSIONS • RELIGIOUS DELUSIONS • SOMATIC DELUSIONS • DELUSIONS OF REFERENCE • DELUSIONS OF BEING CONTROLLED • DELUSIONS OF MIND READING • THOUGHT BROADCASTING • THOUGHT INSERTION • THOUGHT WITHDRAWAL
  12. 12. ITEMS IN THE SCALE FOR THE POSITIVE SYNDROME (SAPS) • BIZARRE BEHAVIOR • CLOTHING AND BEHAVIOR • SOCIAL AND SEXUAL BEHAVIOR • AGGRESSIVE BEHAVIOR • REPETITIVE OR STEREOTYPED BEHAVIOR • POSITIVE FORMAL THOUGHT DISORDER • DERAILMENT • TANGENTIALITY • INCOHERENCE • ILLOGICALITY • CIRCUMSTANTIALITY • PRESSURE OF SPEECH • DISTRACTIBLE SPEECH • CLANGING
  13. 13. NEGATIVE SYMPTOMS • ALOGIA • DYSFUNCTION OF COMMUNICATION; RESTRICTIONS IN THE FLUENCY AND PRODUCTIVITY OF THOUGHT AND SPEECH • AFFECTIVE BLUNTING OR FLATTENING • RESTRICTIONS IN THE RANGE AND INTENSITY OF EMOTIONAL EXPRESSION • ASOCIALITY • REDUCED SOCIAL DRIVE AND INTERACTION • ANHEDONIA • REDUCED ABILITY TO EXPERIENCE PLEASURE • AVOLITION • REDUCED DESIRE, MOTIVATION, OR PERSISTENCE; RESTRICTIONS IN THE INITIATION OF GOAL-DIRECTED BEHAVIOR
  14. 14. ITEMS IN THE SCALE FOR ASSESSMENT OF NEGATIVE SYMPTOMS (SANS) • AFFECTIVE FLATTENING OR BLUNTING • UNCHANGING FACIAL EXPRESSIONS • DECREASED SPONTANEOUS MOVEMENT • PAUCITY OF EXPRESSIVE GESTURE • POOR EYE CONTACT • AFFECTIVE NONRESPONSIVITY • INAPPROPRIATE AFFECT • LACK OF VOCAL INFLECTIONS • ALOGIA • POVERTY OF SPEECH • POVERTY OF CONTENT OF SPEECH • BLOCKING • INCREASED LATENCY OF RESPONSE
  15. 15. ITEMS IN THE SCALE FOR ASSESSMENT OF NEGATIVE SYMPTOMS (SANS) • AVOLITION—APATHY • GROOMING AND HYGIENE • IMPERSISTENCE AT WORK OR SCHOOL • PHYSICAL ANERGIA • ANHEDONIA—ASOCIALITY • RECREATIONAL INTERESTS AND ACTIVITIES • SEXUAL INTEREST AND ACTIVITIES • INTIMACY AND CLOSENESS • RELATIONSHIPS WITH FRIENDS • ATTENTION • SOCIAL INATTENTIVENESS • INATTENTIVENESS DURING TESTING
  16. 16. NEUROBIOLOGY OF PSYCHOSIS • THERE ARE VARIOUS THEORIES REGARDING THE PATHWAYS INVOLVED IN THE DEVELOPMENT OF PSYCHOSIS 2 MAJOR ARE • THE DOPAMINERGIC HYPOTHESIS • THE GLUTAMATE HYPOTHESIS
  17. 17. THE DOPAMINERGIC PATHWAYS • THERE ARE 4 WELL DEFIENED AND A RECENTLY DISCOVERED 5TH DOPAMINERGIC PATHWAYS NAMELY • MESOLIMBIC • MESOCORTICAL • NIGROSTRIATAL • TUBULO-INFUNDIBULAR • THALAMIC • THE HYPER OR HYPODOPAMINERGIC ACTION ON THE FIRST 2 PATHWAYS ARE RESPONSIBLE FOR THE POSITIVE AND NEGATIVE SYMPTOMS OF PSYCHOSIS. • BUT, WE NEED TO HAVE KNOWLEDGE ABOUT THE OTHER PATHWAYS TOO INORDER TO UNDERSTAND THE SIDEEFFECTS OF DRUGS AND MANAGEMENT.
  18. 18. DOPAMINE RECEPTORS There are at least five subtypes of receptors: Receptor • D1 • D2 • D3 • D4 • D5 DOPAMINE SYNAPSE DA L-DOPA TYROSINE TYROSINE www.freelivedoctor.com
  19. 19. THE MESOLIMBIC PATHWAY • ORIGIN: • DOPAMINERGIC CELL BODIES IN THE VENTRAL TEGMENTAL AREA OF THE BRAINSTEM • PROJECTS TO: • AXON TERMINALS OF THE NUCLEUS ACCUMBENS IN THE VENTRAL STRIATUM.
  20. 20. MESOLIMBIC PATHWAY
  21. 21. • RESPONSIBLE FOR: • IN NORMAL PERSON • EMOTIONAL BEHAVIOUR • MOTIVATION • PLEASURE • REWARD • IN PSYCHOSIS: • POSITIVE SYMPTOMS SUCH AS DELUSIONS AND HALLUCINATIONS • ANHEDONIA • LACK OF PLEASURE AND MOTIVATION
  22. 22. • IT IS BELIEVED THAT IT IS HYPERACTIVITY SPECIFICALLY IN THIS PARTICULAR DOPAMINE PATHWAY THAT MEDIATES THE POSITIVE SYMPTOMS OF PSYCHOSIS. • HYPERACTIVITY OF MESOLIMBIC DOPAMINE NEURONS MAY ALSO PLAY A ROLE IN AGGRESSIVE AND HOSTILE SYMPTOMS IN SCHIZOPHRENIA AND RELATED ILLNESSES, ESPECIALLY IF SEROTONERGIC CONTROL OF DOPAMINE IS ABERRANT IN PATIENTS WHO LACK IMPULSE CONTROL.
  23. 23. THE MESOCORTICAL PATHWAY • ORIGIN: • DOPAMINERGIC CELL BODIES OF THE VENTRAL TEGMENTAL AREA PROJECTS TO:
  24. 24. • DORSOLATERAL PREFRONTAL CORTEX PATHWAY: • IN NORMAL PERSON • REGULATES COGNITION AND EXECUTIVE FUNCTION • IN PSYCHOSIS – HYPODOPAMINERGIC ACTIVITY • NEGATIVE SYMPTOMS • COGNITIVE AND EXECUTIVE FUNCTION DEFICIT • VENTROMEDIAL PREFRONTAL CORTEX PATHWAY: • IN NORMAL PERSON • REGULATES EMOTIONS AND AFFECT • IN PSYCHOSIS– HYPODOPAMINERGIC ACTIVITY • AFFECTIVE SYMPTOMS • NEGATIVE SYMPTOMS
  25. 25. MESOCORTICAL PATHWAY HYPODOPAMINERGIC DLPFC OFC
  26. 26. NIGROSTRIATAL DOPAMINERGIC PATHWAY • ORIGIN: • CELL BODIES IN THE PARS COMPACTA OF THE SUBSTANTIA NIAGRA • PROJECTS TO • STRIATUM • NIGROSTRIATAL PATHWAY IS A PART OF EXTRAPYRAMIDAL NERVOUS SYSTEM. • THIS PATHWAY IS INVOLVED IN MOTOR PLANNING
  27. 27. HYPERACTIVITY/ HYPOACTIVITY
  28. 28. • DOPAMINE DEFICIENCY IN BASAL GANGLIA: • AKATHISIA • DYSTONIA • DOPAMINE HYPERACTIVITY IN BASAL GANGLIA • HYPERKINETIC MOVEMENT DISORDER: • CHOREA • DYSKINESIA • TICS • CHRONIC BLOCKADE OF D2 RECEPTORS WILL RESULT IN TARDIVE DYSKINESIA
  29. 29. • THIS MOVEMENT DISORDER CAUSES FACIAL AND TONGUE MOVEMENTS, SUCH AS CONSTANT CHEWING, TONGUE PROTRUSIONS, FACIAL GRIMACING, AND ALSO LIMB MOVEMENTS THAT CAN BE QUICK, JERKY, OR CHOREIFORM (DANCING). • D2 RECEPTORS ARE HYPOTHESIZED TO BECOME SUPERSENSITIVE OR TO “UPREGULATE” (I.E., INCREASE IN NUMBER), PERHAPS IN A FUTILE ATTEMPT TO OVERCOME DRUG-INDUCED BLOCKADE OF D2 RECEPTORS IN THE STRIATUM
  30. 30. TUBULOINFUNDIBULAR PATHWAY • ORIGIN • HYPOTHALAMUS • PROJECTS TO • ANTERIOR PITUTARY
  31. 31. • NORMALLY THESE NEURONES ARE ACTIVE AND THEY INHIBIT PROLACTIN RELEASE IN POSTPARTUM STATE, ACTIVITY DECREASES PROLACTIN INCREASES LACTATION OCCURS INCREASED PROLACTIN RESULTS IN
  32. 32. THE THALAMIC PATHWAY • ORIGIN • ARISES FROM MULTIPLE SITES, INCLUDING THE • PERIAQUEDUCTAL GRAY • VENTRAL MESENCEPHALON • HYPOTHALAMIC NUCLEI • LATERAL PARABRACHIAL NUCLEUS • PROJECTS TO • THALAMUS
  33. 33. • FUNCTION • ITS FUNCTION IS NOT CURRENTLY WELL KNOWN • MAY BE INVOLVED IN SLEEP AND AROUSAL MECHANISMS
  34. 34. GLUMATE PATHWAYS • THERE ARE 5 GLUTAMATE PATHWAYS • CORTICOBRAINSTEM GLUTAMATE PATHWAY • CORTICOSTRIATAL GLUTAMATE PATHWAY • THALAMOCORTICAL GLUTAMATE PATHWAY • CORTICOTHALAMIC GLUTAMATE PATHWAY • CORTICOCORTICAL GLUTAMATE PATHWAY • ALL OF THEM ARE PRESENT IN PREFRONTAL CORTEX.
  35. 35. CORTICOBRAINSTEM GLUTAMATE PATHWAY • ORIGIN: • CORTICAL PYRAMIDAL NEURONES, MOSTLY IN LAMINA 5 • PROJECTS TO • BRAINSTEM NEUROTRANSMITTER CENTRES • RAPHE NUCLEUS FOR SEROTONIN • VENTRAL TEGMENTAL ARE AND SUBSTANTIA NIAGRA FOR DOPAMINE • LOCUS COERULEUS FOR NOREPINEPHRINE
  36. 36. CORTICOBRAINSTEM GLUTAMATE PATHWAY CORTICAL PYRAMIDAL NEURONES, MOSTLY IN LAMINA 5 BRAINSTEM NEUROTRANSMITTER CENTRES
  37. 37. ACTION • ACTS AS A BRAKE ON THE MESOLIMBIC DOPAMINE PATHWAY (MLDP) HOW ? • IT CONNECTS THE MLDP WITH AN INHIBITORY GABA INTERNEURONE IN VTA. • THUS IT DECREASES DOPAMINE WHEN ACTIVATED • HENCE, WHEN THIS PATHWAY MALFUNCTIONS, THERE IS HYPERDOPAMINERGIC ACTION IN MLDP RESULTING IN POSITIVE SYMPTOMS
  38. 38. ANOTHER HYPOTHESIS • A MAJOR CURRENT HYPOTHESIS FOR SCHIZOPHRENIA INVOLVES NMDA RECEPTORS IN THIS PATHWAY. • THE NMDA RECEPTOR HYPOFUNCTION HYPOTHESIS OF SCHIZOPHRENIA ARISES FROM OBSERVATIONS THAT WHEN NMDA RECEPTORS ARE MADE HYPOFUNCTIONAL BY MEANS OF THE NMDA RECEPTOR ANTAGONIST PHENCYCLIDINE (PCP) • THIS PRODUCES A PSYCHOTIC CONDITION IN NORMAL HUMANS VERY SIMILAR TO THE POSITIVE SYMPTOMS OF SCHIZOPHRENIA, INCLUDING HALLUCINATIONS AND DELUSIONS
  39. 39. WHAT IS THE HYPOTHESIS ? NMDA RECEPTORS SPECIFICALLY IN THE CORTICOBRAINSTEM GLUTAMATE PROJECTION MIGHT BE HYPOACTIVE IN UNTREATED SCHIZOPHRENIA THUS CANNOT DO THEIR JOB OF TONICALLY INHIBITING MESOLIMBIC DOPAMINE NEURONS. WHEN THIS HAPPENS, MESOLIMBIC DOPAMINE HYPERACTIVITY IS THE RESULT.
  40. 40. • IT HAS BEEN SEEN THAT PCP ALSO MIMICS THE COGNITIVE, NEGATIVE AND AFFECTIVE SYMPTOMS • THESE ADDITIONAL CLINICAL OBSERVATIONS HAVE LED TO THE IDEA THAT NMDA RECEPTORS IN CORTICOBRAINSTEM GLUTAMATE PROJECTIONS THAT REGULATE MESOCORTICAL DOPAMINE PATHWAYS MAY ALSO BE HYPOACTIVE
  41. 41. NORMALLY, THE DESCENDING CORTICOBRAINSTEM GLUTAMATE NEURONS ACT AS ACCELERATORS TO MESOCORTICAL DOPAMINE NEURONS CORTICOBRAINSTEM GLUTAMATE NEURONS SYNAPSE DIRECTLY ON THOSE DOPAMINE NEURONS IN THE VENTRAL TEGMENTAL AREA THAT PROJECT TO THE CORTEX THIS MEANS THAT CORTICOBRAINSTEM GLUTAMATE NEURONS NORMALLY FUNCTION AS ACCELERATORS OF THESE MESOCORTICAL DOPAMINE NEURONS; THEREFORE THEY EXCITE THEM TONICALLY NMDA RECEPTOR HYPOACTIVITY THEY LOSE THEIR EXCITATORY DRIVE AND BECOME HYPOACTIVE COGNITIVE, NEGATIVE, AND AFFECTIVE SYMPTOMS
  42. 42. CORTICOSTRIATAL GLUTAMATE PATHWAY • ORIGIN • PYRAMIDAL NEURONES OF CORTEX (LAMINA 5) • PROJECTS TO: STRIATUM THALAMUS IF PROJECTS TO NUCLEUS ACCUMBENS, ITS CALLED CORTICOACCUMBENS GLUTAMATE PATHWAY
  43. 43. • NORMALLY, THIS CORTICOSTRIATAL GLUTAMATE PROJECTION TO THE STRIATUM TERMINATES ON GABA NEURONS IN THE STRIATUM • THESE GABA NEURONES IN THE THE THALAMUS CREATES A KIND OF SENSORY FILTER TO PREVENT TOO MUCH OF SENSORY TRAFFIC COMING INTO THE THALAMUS FROM ESCAPING TO THE CORTEX, WHERE IT MAY CONFUSE OR OVERWHELM CORTICAL INFORMATION PROCESSING.
  44. 44. PYRAMIDAL GLUTAMINERGIC NEURONS DESCEND FROM THE PREFRONTAL CORTEX TO THE STRIATUM, WHERE THEY TERMINATE ON GABA NEURONS GABA PROJECTION TO THE THALAMUS THALAMOCORTICAL GLUTAMATE NEURONS THAT PROJECT BACK TO THE ORIGINAL CORTICAL PYRAMIDAL NEURON
  45. 45. THALAMOCORTICAL GLUTAMATE PATHWAY • ORIGIN: • THALAMUS • INNERVATES: • PYRAMIDAL NEURONES IN CORTEX • IT IS ACTUALLY THE RETURNING LEG OF THE CSTC LOOP.
  46. 46. NMDA RECEPTOR HYPOFUNCTION + INCREASED MESOLIMBIC DOPAMINE DRIVE FAILURE OF THALAMIC FILTERS EXCESS INFORMATION ESCAPES TO CORTEX HALLUCINATIONS, COGNITIVE, AFFECTIVE SYMPTOMS
  47. 47. DOPAMINERGIC INPUT TO THE NUCLEUS ACCUMBENS VIA THE MESOLIMBIC DOPAMINE PATHWAY INHIBITORY EFFECT ON GABA NEURONS REDUCED STIMULATORY GLUTAMATERGIC INPUT TO THESE NEURONS FROM THE PREFRONTAL CORTEX THEREBY REDUCES THE EFFECTIVENESS OF THE THALAMIC SENSORY FILTER SINCE LESS GABA IS RELEASED MORE SENSORY INPUT CAN ESCAPE FROM THE THALAMUS TO THE CORTEX • CAUSES INCREASED CORTICAL ACTIVATION • OVERLOAD IN THE PREFRONTAL CORTEX • POSITIVE SYMPTOMS
  48. 48. CORTICOTHALAMIC GLUTAMATE PATHWAY • ORIGIN • LAMINA 6 IN CORTEX • PROJECTS • THALAMUS
  49. 49. CORTICOCORTICAL GLUTAMATE PATHWAY • ORIGIN • CORTICAL PYRAMIDAL NEURONES • PROJECTS • CORTICAL PYRAMIDAL NEURONES • CORTICAL PYRAMIDAL NEURONES THUS UTILIZE GLUTAMATE TO COMMUNICATE BACK AND FORTH
  50. 50. ROLE OF ANTIPSYCHOTICS • THE MAIN MECHANISM OF ACTION OF ANY ANTIPSYCHOTIC IS BLOCKADE OF DOPAMINE RECEPTORS. • ANTIPSYCHOTICS ARE BROADLY CLASSIFIED INTO 2 GROUPS: A) TYPICAL ANTIPSYCHOTICS B) ATYPICAL ANTIPSYCHOTICS
  51. 51. • TYPICAL ANTIPSYCHOTICS • PHENOTHIAZINES (CHLORPROMAZINE, PERPHENAZINE, FLUPHENAZINE, THIORIDAZINE ET AL) • THIOXANTHENES (FLUPENTHIXOL, CLOPENTHIXOL) • BUTYROPHENONES (HALOPERIDOL, DROPERIDOL)
  52. 52. WHAT MAKES AN ANTIPSYCHOTIC TYPICAL ? • D2 RECEPTOR ANTAGONISM. • MUSCARINIC CHOLINERGIC BLOCKING PROPERTIES
  53. 53. • WHAT DOES D2 RECEPTOR ANTAGONISM DO ? • CONVENTIONAL ANTIPSYCHOTICS SEEK OUT AND BLOCK ALMOST EVERY D2 RECEPTOR IN BRAIN • DUE TO BLOCKADE OF D2 RECEPTORS IN • MESOLIMBIC DOPAMINERGIC TRACT • DECREASE IN POSITIVE SYMPTOMS • BLOCKADE OF REWARD MECHANISM RESULTING IN ANHEDONIA, APATHY, AMOTIVATION • MESOCORTICAL DOPAMINERGIC TRACT • WORSENING OF NEGATIVE SYMPTOMS
  54. 54. • NIGROSTRIATAL PATHWAY • DYSTONIA • AKATHISIA • DRUG INDUCED PARKINSONISM • TARDIVE DYSKINESIA • TUBULOINFUNDIBULAR PATHWAY • GALACTORRHOEA • SEXUAL DYSFUNCTION • INFERTILITY
  55. 55. HOW MUSCARINIC CHOLINERGIC RECEPTOR ACTIVATION CAUSES EXTRAPYRAMIDAL SYMPTOMS ? • DOPAMINE AND ACETYLCHOLINE HAS RECIPROCAL RELATIONSHIP WITH EACH OTHER IN THE NIGROSTRIATAL PATHWAY. • DOPAMINE NEURONES MAKE POSTSYNAPTIC CONNECTIONS WITH CHOLINERGIC NEURONES. DOPAMINE NEURONE CHOLINERGIC NEURONE M1 RECEPTOR
  56. 56. ANTIPSYCHOTIC USED D2 BLOCKADE DECREASED DOPAMINE DECREASED BLOCKING OF CHOLINERGIC NEURONES INCREASED ACETYLCHOLINE EXTRAPYRAMIDAL SYMPTOMS
  57. 57. SO, • MORE DOPAMINE = LESS ACETYLCHOLINE • LESS DOPAMINE = MORE ACETYLCHOLINE • LESS ACETYLCHOLINE = LESS EPS • MORE ACETYLCHOLINE = MORE EPS
  58. 58. MORE ACETYLCHOLINE RELEASE DOPAMINE NEURONE CHOLINERGIC NEURONE DOPAMINE NEURONE CHOLINERGIC NEURONE ATYPICAL ANTIPSYCHOTIC TYPICAL ANTIPSYCHOTIC MORE D2 RECEPTOR BLOCKADE, LESS DOPAMINE RELEASE LESS DOPAMINE LEADS TO LESS CHOLINERGIC BLOCKADE LESS D2 RECEPTOR BLOCKADE, MORE DOPAMINE RELEASE MORE DOPAMINE LEADS TO MORE CHOLINERGIC BLOCKADE LESS ACETYLCHOLINE RELEASE
  59. 59. • HENCE, • TYPICAL ANTIPSYCHOTICS HAVE MORE EXTRAPYRAMIDAL SIDEEFFECTS THAN ATYPICAL ANTIPSYCHOTICS • ONE COMPENSATION FOR THE OVERACTIVITY THAT OCCURS WHEN DOPAMINE RECEPTORS ARE BLOCKED IS TO BLOCK THE ACETYLCHOLINE RECEPTORS WITH AN ANTICHOLINERGIC AGENT (M1 RECEPTORS). • THUS, ANTICHOLINERGICS OVERCOME EXCESS ACETYLCHOLINE ACTIVITY CAUSED BY REMOVAL OF DOPAMINE INHIBITION WHEN DOPAMINE RECEPTORS ARE BLOCKED BY CONVENTIONAL ANTIPSYCHOTICS. • THIS ALSO MEANS THAT EXTRAPYRAMIDAL SYMPTOMS (EPS) ARE REDUCED.
  60. 60. THIS CAN CAUSE UNDESIRABLE SIDE EFFECTS SUCH AS DRY MOUTH, BLURRED VISION, CONSTIPATION, AND COGNITIVE BLUNTING DIFFERING DEGREES OF MUSCARINIC CHOLINERGIC BLOCKADE MAY ALSO EXPLAIN WHY SOME CONVENTIONAL ANTIPSYCHOTICS HAVE A LESSER PROPENSITY TO PRODUCE EXTRAPYRAMIDAL SIDE EFFECTS (EPS) THAN OTHERS. THOSE CONVENTIONAL ANTIPSYCHOTICS THAT CAUSE MORE EPS ARE THE AGENTS THAT HAVE ONLY WEAK ANTICHOLINERGIC PROPERTIES, WHEREAS THOSE CONVENTIONAL ANTIPSYCHOTICS THAT CAUSE FEWER EPS ARE THE AGENTS THAT HAVE STRONGER ANTICHOLINERGIC PROPERTIES. MAY HAVE M1 ANTIMUSCARINIC PROPERTY
  61. 61. • ANTIPSYCHOTICS MAY HAVE H1 RECEPTOR BLOCKING PROPERTY • WEIGHT GAIN • DROWSINESS
  62. 62. • MAY HAVE α1 ANTIADRENERGIC PROPERTIES • DROWSINESS • ORTHOSTATIC HYPOTENSION
  63. 63. 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.
  64. 64. 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.
  65. 65. • TREATMENT • VIGOROUS TREATMENT WITH ANTIPARKINSONIAN DRUGS IS RECOMMENDED AS SOON AS POSSIBLE. • MUSCLE RELAXANTS SUCH AS DIAZEPAM, DANTROLENE OR BROMOCRIPTINE MAY BE HELPFUL.
  66. 66. TYPICAL ANTIPSYCHOTICS
  67. 67. WHAT MAKES ANTIPSYCHOTICS ATYPICAL ? • LOW EPS • GOOD FOR NEGATIVE SYMPTOMS • THEY USUALLY HAVE 4 TYPES OF ACTIONS: • SEROTONIN DOPAMINE ANTAGONISM • D2 ANTAGONISM WITH RAPID DISSOCIATION • D2 PARTIAL AGONISM • SEROTONIN PARTIAL AGONISM
  68. 68. SEROTONIN RECEPTORS • PRESYNAPTIC - 5HT1A AND 5HT1B/1D • POSTSYNAPTIC – 5HT1A, 5HT1B/1D, 5HT2A, 5HT2C, 5HT3, 5HT4, 5HT5, 5HT6, 5HT7 • 5HT1A – SOMATODENDRITIC AUTORECEPTORS • 5HT1B/1D – TERMINAL AUTORECEPTORS
  69. 69. 5HT1A INHIBITS CORTICAL PYRAMIDAL NEURONE REGULATES HORMONES, COGNITION, ANXIETY, DEPRESSION 5HT2A EXCITES CORTICAL PYRAMIDAL NEURONES ENHANCES GLUTAMATE RELEASE SLEEP AND HALLUCINATION REGULATION 5HT2C REGULATES DOPAMINE & NOREPINEPHRINE OBESITY, MOOD, COGNITION 5HT3 REGULATES INHIBITORY INTERNEURONES IN CORTEX MEDIATES VOMITING VIA VAGAL NERVE 5HT6 UNDER INVESTIGATION REGULATES RELEASE OF BDNF -> FORMATION OF LONG TERM MEMORY 5HT7 UNDER INVESTIGATION REGULATES CIRCADIAN RHYTHM, SLEEP, MOOD
  70. 70. • 5HT1A AND 5HT2A HAVE OPPOSITE ACTION IN REGULATING DOPAMINE RELEASE. 5HT1A SOMATODENDRITIC AUTORECEPTORS 5HT1B/1D 5HT1B/1D TERMINAL AUTORECEPTORS GABA DA DA 5HT2AX SEROTONIN IN ABSENCE OF SEROTONIN THERE IS NO ACTIVATION OF THESE RECEPTORS, RESULTING IN UNINHIBITED ACTION OF THE SEROTONERGIC NEURONES EXCESS SEROTONIN IN THE SYNAPSE RESULTS IN ACTIVATION OF THE 5HT1A/1B TERMINAL AUTORECEPTORS, WHICH INHIBITS SEROTONIN RELEASE
  71. 71. • MANY ANTIPSYCHOTICS ARE ANTAGONISTS AT THE 5HT2A RECEPTOR AS WELL AS THE D2 RECEPTORS. • THIS ANTAGONISTIC ACTION MAY BE A KIND OF INVERSE AGONIST. HOW SEROTONIN DOPAMINE ANTAGONISTS ACT ?
  72. 72. DA NEURONE DA NEURONE OF NIGROSTRIATAL TRACT 5HT NEURONE CAPSULE SDA MOLECULES RELEASED SDA BINDS AT THE 5HT2A RECEPTORS BLOCKING ITS ACTION RESULTING IN MORE DA SECRETION X SEROTONIN BINDS AT 5HT2A RECEPTORS BLOCKS DA SECRETION DISPLACES SOME SDA FROM ITS BINDING SITE AT D2 RECEPTOR DA ACTS ON D2 RECEPTORS AND DECREASES EPS
  73. 73. 5HT2A ANTAGONISM REDUCES NEGATIVE SYMPTOMS • SOME EXPERTS BELIEVE THAT ATYPICAL ANTIPSYCHOTICS DO NOT REALLY REDUCE NEGATIVE SYMPTOMS BUT THAT CONVENTIONAL ANTIPSYCHOTICS INCREASE THEM. • NEGATIVE SYMPTOMS OF SCHIZOPHRENIA IS BECAUSE OF RELATIVE DEFICIENCY IN DOPAMINE EITHER DUE TO: • PRIMARY DEFICIENCY • VARIOUS OTHER SECONDARY CAUSES SUCH AS 5HT EXCESS • IN EITHER CASE, BLOCKADE OF 5HT2A RECEPTORS WITH ATYPICAL ANTIPSYCHOTICS SHOULD LEAD TO DA RELEASE WHICH COULD COMPENSATE FOR THE DA DEFICIENCY AND IMPROVE AFFECTIVE, COGNITIVE & NEGATIVE SYMPTOMS
  74. 74. 5HT2A ANTAGONISM MAY IMPROVE POSITIVE SYMPTOMS • 5HT1A AND 5HT2A RECEPTORS ALONG WITH DOPAMINE HAS EFFECT ON GLUTAMATE RELEASE • 5HT1A INHIBIT GLUTAMATE RELEASE • 5HT2A ACCLERATES GLUTAMATE RELEASE
  75. 75. • IT IS POSSIBLE THAT STIMULATORY EFFECT OF 5HT2A RECEPTORS ON GLUTAMATE RELEASE MAY BE LINKED TO CAUSATION OF HALLUCINATION • HALLUCINOGENS ARE PARTIAL AGONIST AT 5HT2A
  76. 76. ACTIVATED BY 5HT RELEASE OF GLUTAMATE SEROTONIN 5HT2A 5HT1A 5HT2A INHIBITOR ACTIVATED BY 5HT INHIBITION OF GLUTAMATE RELEASE XX 3 NEURONE CIRCUIT MODEL SEROTONERGIC NEURONES GLUTAMINERGIC NEURONE
  77. 77. • ITS HAS BEEN FOUND THERE IS ABNORMAL ACTIVATION OF 5HT2A RECEPTORS ON CORTICAL GLUTAMATE NEURONES IN HALLUCINOGEN ABUSE AS WELL AS SCHIZOPHRENIA • THIS HAS SUGGESTED THE IDEA OF ADDING A PURE 5HT2A RECEPTOR ANTAGONIST WITH CONVENTIONAL ANTIPSYCHOTICS OR EVEN ATYPICAL ANTIPSYCHOTICS FOR BETTER RESULTS AND UNWANTED SIDEEFFECTS AVOIDANCE
  78. 78. • IDEAL GOAL: • 70 – 80% BLOCKADE OF D2 RECEPTORS IN MESOLIMBIC PATHWAY • COMPLETE BLOCKADE OF MESOCORTICAL 5HT2A RECEPTORS • EXAMPLE OF SELECTIVE 5HT2A RECEPTOR ANTAGONIST, ACTUALLY AN INVERSE AGONIST ACP 103 (ENHANCES THE EFFICACY OF RISPERIDONE IN SCHIZOPHRENIA)
  79. 79. ROLE OF 5HT2A ANTAGONISTS IN HYPERPROLACTINEMIA • DOPAMINE INHIBITS PROLACTIN RELEASE BY STIMULATING D2 RECEPTORS DOPAMINE INHIBITS PROLACTIN RELEASE FROM PITUITARY LACTOTROPH CELLS IN THE PITUITARY GLAND WHEN IT BINDS TO D2 RECEPTORS
  80. 80. • SEROTONIN PROMOTES PROLACTIN RELEASE BY STIMULATING 5HT2A RECEPTORS SEROTONIN (5HT) STIMULATES PROLACTIN RELEASE FROM PITUITARY LACTOTROPH CELLS IN THE PITUITARY GLAND WHEN IT BINDS TO 5HT2A RECEPTORS. THUS, SEROTONIN AND DOPAMINE HAVE A RECIPROCAL REGULATORY ACTION ON PROLACTIN RELEASE.
  81. 81. CONVENTIONAL ANTIPSYCHOTICS AND PROLACTIN • CONVENTIONAL ANTIPSYCHOTIC DRUGS ARE D2 ANTAGONISTS • THUS OPPOSE DOPAMINE'S INHIBITORY ROLE ON PROLACTIN SECRETION FROM PITUITARY LACTOTROPHS. THUS, THESE DRUGS INCREASE PROLACTIN LEVELS
  82. 82. ATYPICAL ANTIPSYCHOTICS AND PROLACTIN. • SEROTONIN 5HT2A ANTAGONISM REVERSES THE ABILITY OF D2 ANTAGONISM TO INCREASE PROLACTIN SECRETION. • AS DOPAMINE AND SEROTONIN HAVE RECIPROCAL REGULATORY ROLES IN THE CONTROL OF PROLACTIN SECRETION, ONE CANCELS THE OTHER. • THUS, STIMULATING 5HT2A RECEPTORS REVERSES THE EFFECTS OF STIMULATING D2 RECEPTORS. • THE SAME THING WORKS IN REVERSE, NAMELY, BLOCKADE OF 5HT2A RECEPTORS REVERSES THE EFFECTS OF BLOCKING D2 RECEPTORS
  83. 83. D2 ANTAGONISM WITH RAPID DISSOCIATION • AN ANTIPSYCHOTIC IS ATYPICAL BY ITS PROPERTY OF RAPID DISSOCIATION FROM D2 RECEPTORS. • THIS IS ALSO CALLED HIT-AND-RUN RECEPTOR BINDING PROPERTY
  84. 84. • BECAUSE OF THEIR BIOCHEMICAL NATURE, THE BINDING OF ATYPICAL ANTIPSYCHOTICS TO POSTSYNAPTIC D2 RECEPTORS IS LOOSE, THAT DOES NOT FIT INTO THE TEETH OF THE RECEPTOR. • FIRST STAGE OF HIT-AND-RUN BINDING: THE HIT • HERE THE ATYPICAL ANTIPSYCHOTIC IS BINDING TO THE D2 RECEPTOR. • IT FITS LOOSELY INTO THE D2 RECEPTOR WITHOUT GETTING LOCKED INTO THE GROOVES OF THE RECEPTOR AS DO THE CONVENTIONAL ANTIPSYCHOTICS. • SECOND STAGE OF HIT-AND-RUN BINDING: THE RUN • SINCE AN ATYPICAL ANTIPSYCHOTIC FITS LOOSELY INTO THE D2 RECEPTORS, IT SLIPS OFF EASILY AFTER BINDING ONLY BRIEFLY AND THEN RUNS AWAY. • THIS IS ALSO CALLED RAPID DISSOCIATION.
  85. 85. D2 PARTIAL AGONISM (DPA) MAKES AN ANTIPSYCHOTIC ATYPICAL • A NEW CLASS OF ANTIPSYCHOTICS IS EMERGING THAT STABILIZES DOPAMINE NEUROTRANSMISSION IN A STATE BETWEEN SILENT ANTAGONISM AND FULL STIMULATION. • THIS IS DUE TO PARTIAL AGONIST ACTIONS AT THE D2 RECEPTOR • DOPAMINE PARTIAL AGONISTS (DPAS) THEORETICALLY BIND TO THE D2 RECEPTOR IN A MANNER THAT IS NEITHER TOO ANTAGONIZING, LIKE A CONVENTIONAL ANTIPSYCHOTIC, NOR TOO STIMULATING, LIKE A STIMULANT OR DOPAMINE ITSELF.
  86. 86. • INSTEAD, A PARTIAL AGONIST BINDS IN AN INTERMEDIARY MANNER, WITH ANTIPSYCHOTIC ACTIONS BUT NO EPS. • FOR THIS REASON, PARTIAL AGONISTS THAT GET THE BALANCE BETWEEN FULL AGONISM AND COMPLETE ANTAGONISM ARE SOMETIMES CALLED "GOLDILOCKS" DRUGS.
  87. 87. 5HT1A PARTIAL AGONIST (SPA) ACTIONS MAKE AN ANTIPSYCHOTIC ATYPICAL • AGONIST ACTIONS AT 5HT1A RECEPTORS • INCREASE IN DOPAMINE RELEASE AND REDUCTION IN GLUTAMATE RELEASE. • ENHANCED DOPAMINE RELEASE BY SPA ACTS IN THE STRIATUM • IMPROVE EXTRAPYRAMIDAL ACTIONS • ENHANCED DOPAMINE RELEASE BY SPA ACTS • IN THE PITUITARY - THEORETICALLY REDUCE THE RISK OF HYPERPROLACTINEMIA • IN THE PREFRONTAL CORTEX - THEORETICALLY IMPROVE NEGATIVE, COGNITIVE, AND AFFECTIVE SYMPTOMS OF SCHIZOPHRENIA.
  88. 88. • REDUCED GLUTAMATE RELEASE BY SPA - IN PREFRONTAL CORTEX COULD THEORETICALLY REDUCE POSITIVE SYMPTOMS. • THUS, 5HT1A AGONIST ACTION HAS SIMILAR NET EFFECTS TO 5HT2A ANTAGONISM. • SOME DRUGS HAVE BOTH 5HT1A AGONIST ACTIONS AND 5HT2A ANTAGONIST ACTIONS, AN ACTION THAT COULD BE ADDITIVE OR SYNERGISTIC. • OTHER DRUGS HAVE SPA ACTIONS WITHOUT 5HT2A ANTAGONIST ACTIONS
  89. 89. ATYPICAL ANTIPSYCHOTICS IN CLINICAL PRACTICE • ZYPREXA (OLANZAPINE) • SEROQUEL (QUETIAPINE) • GEODON (ZIPRASIDONE) • FANAPT (ILOPERIDONE) • SAPHRIS (ASENAPINE) • RISPERDAL (RISPERIDONE) • INVEGA (PALIPERIDONE) • LATUDA (LURASIDONE) • CLOZARIL (CLOZAPINE) • SOLIAN (AMISULPRIDE) • ASENDIN (AMOXAPINE) • ARIPIPRAZOLE
  90. 90. GLUTAMATE AGONISTS OR ANTAGONISTS FOR TREATMENT OF PSYCHOSIS NMDA ANTAGONISTS • EXCESSIVE GLUTAMATE ACTIVITY COULD LEAD TO EXCITOTOXICITY AND THUS INTERFERE WITH NORMAL NEURODEVELOPMENT • EXCITOTOXICITY COULD ALSO CONTINUE DURING THE COURSE OF THE ILLNESS AND BE LINKED TO DISEASE PROGRESSION IN SCHIZOPHRENIA • HOWEVER, IT IS NOW ALSO WIDELY HYPOTHESIZED THAT ONCE THE ILLNESS OF SCHIZOPHRENIA HAS DEVELOPED, NMDA GLUTAMATE RECEPTORS ARE ACTUALLY HYPOFUNCTIONAL
  91. 91. • BLOCKING EXCESSIVE AND EXCITOTOXIC GLUTAMATE NEUROTRANSMISSION WITH NMDA ANTAGONISTS MIGHT PREVENT DAMAGE OR DEATH TO NEURONS IN SCHIZOPHRENIA • THUS POTENT NMDA ANTAGONISTS MIGHT BLOCK EXCITOTOXICITY, BUT AT A PRICE THAT THEY WOULD ALSO CAUSE OR WORSEN POSITIVE, COGNITIVE, AND NEGATIVE SYMPTOMS OF SCHIZOPHRENIA • LESS ROBUST NMDA ANTAGONISTS SUCH AS MEMANTINE OR EVEN AMANTADINE THAT ONLY PARTIALLY BLOCK NMDA NEUROTRANSMISSION, MIGHT BE BETTER OPTIONS • ANOTHER POSSIBILITY IS TO BLOCK THE PRESYNAPTIC RELEASE OF GLUTAMATE, WHICH IS THE HYPOTHESIZED MECHANISM OF CERTAIN ANTICONVULSANTS THAT ALSO ACT AS MOOD STABILIZERS, LIKE LAMOTRIGINE AND RILUZOLE
  92. 92. AMPAKINES • AMPA (Α-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLE-PROPIONIC ACID) RECEPTORS ARE ONE OF THE GLUTAMATE RECEPTOR SUBTYPES, AND THEY REGULATE ION FLOW AND NEURONAL DEPOLARIZATION THAT CAN LEAD TO NMDA (N-METHYL-D-ASPARTATE) RECEPTOR ACTIVATION. • A NUMBER OF MODULATORS OF THE AMPA RECEPTOR ARE UNDER DEVELOPMENT, INCLUDING THOSE THAT DO NOT ACT DIRECTLY AT THE GLUTAMATE SITE OF THE AMPA RECEPTOR, BUT AT POSITIVE ALLOSTERIC MODULATING (I.E., PAM) SITES ON THIS RECEPTOR • PRELIMINARY EVIDENCE FROM ANIMAL STUDIES SUGGESTS THAT AMPAKINES MIGHT ENHANCE COGNITION • CX546 • CX619/ORG 24448 • ORG 25573 • ORG 25271 • ORG 24292 • ORG 25501 • LY293558 • THESE MIGHT HAVE MORE EFFICACY FOR COGNITIVE SYMPTOMS IN SCHIZOPHRENIA WITHOUT SHOWING ACTIVATION OF POSITIVE SYMPTOMS OR NEUROTOXICITY.
  93. 93. mGluR PRESYNAPTIC ANTAGONISTS/POSTSYNAPTIC AGONISTS • ANOTHER CLASS OF GLUTAMATE RECEPTOR, KNOWN AS METABOTROPIC GLUTAMATE RECEPTORS (mGluR), REGULATES NEUROTRANSMISSION AT GLUTAMATE SYNAPSES • THEY COULD POTENTIALLY PREVENT EXCESSIVE GLUTAMATE RELEASE FROM GLUTAMATE NEURONS AND THEREBY IMPROVE THE SYMPTOMS OF SCHIZOPHRENIA. • ONE SUCH COMPOUND, LY2140023, HAS BEEN TESTED WITH PROOF OF CONCEPT OF EFFICACY IN SCHIZOPHRENIA
  94. 94. GLYCINE AGONIST AGONISTS AT THE GLYCINE SITE OF NMDA RCEPTORS INCLUDE THE NATURALLY OCCURRING AMINO ACIDS GLYCINE AND D-SERINE AN ANALOGUE OF D-SERINE CALLED D-CYCLOSERINE IS ALSO ACTIVE AT THE GLYCINE AGONIST SITE OF NMDA RECEPTORS.
  95. 95. GLYT1 INHIBITORS • GLYCINE TRANSPORTERS ON GLIAL CELLS, KNOWN AS GLYT1, HAS ROLE IN TERMINATING THE ACTION OF GLYCINE RELEASED BY GLIAL CELLS INTO THE SYNAPSES TO ACT AT THE GLYCINE SITE OF NMDA RECEPTORS.
  96. 96. GLYT1 INHIBITORS THE GLYCINE TRANSPORTER 1 (GLYT1) NORMALLY TERMINATES THE ACTIONS OF GLYCINE AT NMDA RECEPTORS IN THE GLUTAMATE SYNAPSE BY TRANSPORTING THE GLYCINE BACK UP INTO GLIAL CELLS AS A REUPTAKE PUMP. INHIBITORS AT GLYT1 WOULD INCREASE AVAILABILITY OF SYNAPTIC GLYCINE, ENHANCING ACTIVITY AT NMDA RECEPTORS. GLYT1 INHIBITION COULD POTENTIALLY IMPROVE COGNITIVE AND NEGATIVE SYMPTOMS OF SCHIZOPHRENIA BY ENHANCING THE AVAILABILITY OF GLYCINE AT HYPOFUNCTIONING NMDA RECEPTORS. SEVERAL GLYT1 INHIBITORS ARE NOW IN CLINICAL TESTING, INCLUDING THE NATURAL AGENT N-METHYLGLYCINE, ALSO KNOWN AS SARCOSINE
  97. 97. SUMMARY • MENTAL DISORDER IN WHICH THE THOUGHTS, AFFECTIVE RESPONSE, ABILITY TO RECOGNIZE REALITY, ABILITY TO COMMUNICATE AND RELATE TO OTHERS ARE SUFFICIENTLY IMPAIRED TO INTERFERE GROSSLY WITH THE CAPACITY TO DEAL WITH REALITY IS CALLED PSYCHOSIS • THERE ARE SEVERAL THEORIES BEHIND THE CAUSATION OF PSYCHOSIS AMONG WHICH THE DOPAMINERGIC HYPOTHESIS AND GLUTAMATE HYPOTHESIS HAVE GAINED THE MOST GROUND • HYPERDOPAMINERGIC ACTIVITY IN THE MESOLIMBIC TRACT AND NMDA RECEPTOR HYPOACTIVITY CAUSES POSITIVE SYMPTOMS • HYPODOPAMINERGIC ACTIVITY IN MESOCORTICAL TRACT IS RESPONSIBLE FOR NEGATIVE SYMPTOMS
  98. 98. • ANTIPSYCHOTICS ARE BROADLY DIVIDED IN TYPICAL AND ATYPICAL ANTIPSYCHOTICS. • AN ANTIPSYCHOTIC IS CONSIDERED TYPICAL DEPENDING ON ITS 2 MAIN PROPERTIES : • D2 RECEPTOR ANTAGONISM. • MUSCARINIC CHOLINERGIC BLOCKING PROPERTIES • AN ANTIPSYCHOTIC IS CONSIDERED ATYPICAL WHEN IT CAUSES: • LOW EPS • GOOD FOR NEGATIVE SYMPTOMS • THEY USUALLY HAVE 4 TYPES OF ACTIONS: • SEROTONIN DOPAMINE ANTAGONISM • D2 ANTAGONISM WITH RAPID DISSOCIATION • D2 PARTIAL AGONISM • SEROTONIN PARTIAL AGONISM
  99. 99. • THERE ARE OTHER ANTIPSYCHOTICS IN THE PROCESS OF RESEARCH WHICH INCLUDES • NMDA ANTAGONISTS • AMPAKINES • mGluR PRESYNAPTIC ANTAGONISTS/POSTSYNAPTIC AGONISTS • GLYCINE AGONISTS • GLYT1 INHIBITORS • MAIN TARGET OF ANY ANTIPSYCHOTICS WHICH ARE BEING DEVELOPED THESE DAYS IS TO KEEP EFFICACY THE SAME BUT REDUCE THE SIDE EFFECTS
  100. 100. BIBLIOGRAPHY • COMPREHENSIVE TEXTBOOK OF PSYCHIATRY, VOL 2, KAPLAN AND SADOCK. • SYNOPSIS OF PSYCHIATRY, 10TH EDITION - BENJAMIN J SADOCK & VIRGINIA A SADOCK • ESSENTIAL PSYCHOPHARMACOLOGY BY STEPHEN.M.STAHL • INTERNET SOURCES.
  101. 101. THANK YOU
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A SEMINAR ON THE NEUROBIOLOGY OF PSYCHOSIS AND THE ROLE OF ANTIPSYCHOTICS

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