A SEMINAR ON THE NEUROBIOLOGY OF PSYCHOSIS AND THE ROLE OF ANTIPSYCHOTICS

1. DR. SUBRATA NASKAR
MD Psychiatry Trainee
Email: nsubrata09@gmail.com
Please download the presentation for availability of animation employed.

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. 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. • 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. 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. • 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. 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. 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. 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. POSITIVE SYMPTOMS
• DELUSIONS
• HALLUCINATIONS
• DISTORTIONS OR EXAGGERATIONS IN LANGUAGE AND COMMUNICATION
• DISORGANIZED SPEECH
• DISORGANIZED BEHAVIOR
• CATATONIC BEHAVIOR
• AGITATION
*STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY

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. 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. 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. 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. 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. 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. 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. 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. 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. MESOLIMBIC PATHWAY

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. • 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. THE MESOCORTICAL PATHWAY
• ORIGIN:
• DOPAMINERGIC CELL BODIES OF THE VENTRAL TEGMENTAL AREA
PROJECTS TO:

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. MESOCORTICAL PATHWAY
HYPODOPAMINERGIC
DLPFC
OFC

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. HYPERACTIVITY/ HYPOACTIVITY

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. • 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

31. TUBULOINFUNDIBULAR PATHWAY
• ORIGIN
• HYPOTHALAMUS
• PROJECTS TO
• ANTERIOR PITUTARY

33. • NORMALLY THESE NEURONES ARE ACTIVE AND THEY INHIBIT PROLACTIN
RELEASE
IN POSTPARTUM
STATE, ACTIVITY
DECREASES
PROLACTIN
INCREASES
LACTATION
OCCURS
INCREASED PROLACTIN RESULTS IN

34. THE THALAMIC PATHWAY
• ORIGIN
• ARISES FROM MULTIPLE SITES, INCLUDING THE
• PERIAQUEDUCTAL GRAY
• VENTRAL MESENCEPHALON
• HYPOTHALAMIC NUCLEI
• LATERAL PARABRACHIAL NUCLEUS
• PROJECTS TO
• THALAMUS

35. • FUNCTION
• ITS FUNCTION IS NOT CURRENTLY WELL KNOWN
• MAY BE INVOLVED IN SLEEP AND AROUSAL MECHANISMS

36. 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.

37. 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

38. CORTICOBRAINSTEM GLUTAMATE PATHWAY
CORTICAL PYRAMIDAL NEURONES, MOSTLY IN LAMINA 5
BRAINSTEM NEUROTRANSMITTER CENTRES

39. 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

40. 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

41. 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.

43. • 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

44. 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

45. CORTICOSTRIATAL GLUTAMATE PATHWAY
• ORIGIN
• PYRAMIDAL NEURONES OF CORTEX (LAMINA 5)
• PROJECTS TO:
STRIATUM THALAMUS
IF PROJECTS TO NUCLEUS ACCUMBENS, ITS CALLED CORTICOACCUMBENS GLUTAMATE PATHWAY

46. • 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.

47. 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

48. THALAMOCORTICAL GLUTAMATE PATHWAY
• ORIGIN:
• THALAMUS
• INNERVATES:
• PYRAMIDAL NEURONES IN CORTEX
• IT IS ACTUALLY THE RETURNING LEG OF THE CSTC LOOP.

49. NMDA RECEPTOR HYPOFUNCTION
+
INCREASED MESOLIMBIC DOPAMINE DRIVE
FAILURE OF THALAMIC FILTERS
EXCESS INFORMATION ESCAPES TO CORTEX
HALLUCINATIONS, COGNITIVE, AFFECTIVE SYMPTOMS

50. 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

51. CORTICOTHALAMIC GLUTAMATE PATHWAY
• ORIGIN
• LAMINA 6 IN CORTEX
• PROJECTS
• THALAMUS

52. CORTICOCORTICAL GLUTAMATE PATHWAY
• ORIGIN
• CORTICAL PYRAMIDAL NEURONES
• PROJECTS
• CORTICAL PYRAMIDAL NEURONES
• CORTICAL PYRAMIDAL NEURONES THUS UTILIZE GLUTAMATE TO
COMMUNICATE BACK AND FORTH

55. 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

56. • TYPICAL ANTIPSYCHOTICS
• PHENOTHIAZINES (CHLORPROMAZINE, PERPHENAZINE, FLUPHENAZINE,
THIORIDAZINE ET AL)
• THIOXANTHENES (FLUPENTHIXOL, CLOPENTHIXOL)
• BUTYROPHENONES (HALOPERIDOL, DROPERIDOL)

57. WHAT MAKES AN ANTIPSYCHOTIC TYPICAL ?
• D2 RECEPTOR ANTAGONISM.
• MUSCARINIC CHOLINERGIC BLOCKING PROPERTIES

58. • 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

59. • NIGROSTRIATAL PATHWAY
• DYSTONIA
• AKATHISIA
• DRUG INDUCED PARKINSONISM
• TARDIVE DYSKINESIA
• TUBULOINFUNDIBULAR PATHWAY
• GALACTORRHOEA
• SEXUAL DYSFUNCTION
• INFERTILITY

60. 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

61. ANTIPSYCHOTIC
USED
D2 BLOCKADE
DECREASED
DOPAMINE
DECREASED
BLOCKING OF
CHOLINERGIC
NEURONES
INCREASED
ACETYLCHOLINE
EXTRAPYRAMIDAL
SYMPTOMS

62. SO,
• MORE DOPAMINE = LESS ACETYLCHOLINE
• LESS DOPAMINE = MORE ACETYLCHOLINE
• LESS ACETYLCHOLINE = LESS EPS
• MORE ACETYLCHOLINE = MORE EPS

63. 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

64. • 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.

65. 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

66. • ANTIPSYCHOTICS MAY HAVE H1 RECEPTOR BLOCKING PROPERTY
• WEIGHT GAIN
• DROWSINESS

67. • MAY HAVE α1 ANTIADRENERGIC PROPERTIES
• DROWSINESS
• ORTHOSTATIC HYPOTENSION

68. 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.

69. 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.

70. • TREATMENT
• VIGOROUS TREATMENT WITH ANTIPARKINSONIAN DRUGS IS RECOMMENDED
AS SOON AS POSSIBLE.
• MUSCLE RELAXANTS SUCH AS DIAZEPAM, DANTROLENE OR BROMOCRIPTINE
MAY BE HELPFUL.

71. TYPICAL ANTIPSYCHOTICS

72. 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

73. 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

74. 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

75. • 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

76. • 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 ?

77. 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

78. 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

79. 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

80. • 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

81. 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

82. • 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

83. • 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)

84. 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

85. • 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.

86. 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

87. 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

88. 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

89. • 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.

90. 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.

91. • 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.

92. 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.

93. • 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

94. 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

95. 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

96. • 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

97. 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.

98. 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

99. 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.

100. 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.

101. 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

102. 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

103. • 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

104. • 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

105. 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.

106. THANK YOU