DR. SUBRATA NASKAR

MD Psychiatry Trainee

Email: nsubrata09@gmail.com

Please download the presentation for availability of animation employed.

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

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

• 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

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.

• 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

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”

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

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

POSITIVE SYMPTOMS

• DELUSIONS

• HALLUCINATIONS

• DISTORTIONS OR EXAGGERATIONS IN LANGUAGE AND COMMUNICATION

• DISORGANIZED SPEECH

• DISORGANIZED BEHAVIOR

• CATATONIC BEHAVIOR

• AGITATION

*STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY

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

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

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

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

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

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

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.

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

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.

MESOLIMBIC PATHWAY

• 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

• 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.

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 – 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

MESOCORTICAL PATHWAY

HYPODOPAMINERGIC

DLPFC

OFC

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

HYPERACTIVITY/ HYPOACTIVITY

• 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

• 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

TUBULOINFUNDIBULAR PATHWAY

•ORIGIN• HYPOTHALAMUS

•PROJECTS TO • ANTERIOR PITUTARY

• NORMALLY THESE NEURONES ARE ACTIVE AND THEY INHIBIT PROLACTIN RELEASE

IN POSTPARTUM STATE, ACTIVITY

DECREASES

PROLACTIN INCREASES

LACTATION OCCURS

INCREASED PROLACTIN RESULTS IN

THE THALAMIC PATHWAY

• ORIGIN• ARISES FROM MULTIPLE SITES, INCLUDING THE

• PERIAQUEDUCTAL GRAY

• VENTRAL MESENCEPHALON

• HYPOTHALAMIC NUCLEI

• LATERAL PARABRACHIAL NUCLEUS

• PROJECTS TO• THALAMUS

• 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

• THALAMOCORTICAL GLUTAMATE PATHWAY

• CORTICOTHALAMIC GLUTAMATE PATHWAY

• CORTICOCORTICAL GLUTAMATE PATHWAY

• ALL OF THEM ARE PRESENT IN PREFRONTAL CORTEX.

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

CORTICOBRAINSTEM GLUTAMATE PATHWAYCORTICAL 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 INTERNEURONE IN VTA.

• THUS IT DECREASES DOPAMINE WHEN ACTIVATED

• HENCE, WHEN THIS PATHWAY MALFUNCTIONS, THERE IS HYPERDOPAMINERGIC ACTION IN MLDP RESULTING IN POSITIVE SYMPTOMS

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

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.

• 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

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

CORTICOSTRIATAL GLUTAMATE PATHWAY

• ORIGIN

• PYRAMIDAL NEURONES OF CORTEX (LAMINA 5)

• PROJECTS TO:

STRIATUM THALAMUS

IF PROJECTS TO NUCLEUS ACCUMBENS, ITS CALLED CORTICOACCUMBENS GLUTAMATE PATHWAY

• 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.

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

THALAMOCORTICAL GLUTAMATE PATHWAY

• ORIGIN:• THALAMUS

• INNERVATES:• PYRAMIDAL NEURONES IN CORTEX

• IT IS ACTUALLY THE RETURNING LEG OF THE CSTC LOOP.

NMDA RECEPTOR HYPOFUNCTION

+

INCREASED MESOLIMBIC DOPAMINE DRIVE

FAILURE OF THALAMIC FILTERS

EXCESS INFORMATION ESCAPES TO CORTEX

HALLUCINATIONS, COGNITIVE, AFFECTIVE SYMPTOMS

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

CORTICOTHALAMIC GLUTAMATE PATHWAY

• ORIGIN

• LAMINA 6 IN CORTEX

• PROJECTS

• THALAMUS

CORTICOCORTICAL GLUTAMATE PATHWAY

• ORIGIN• CORTICAL PYRAMIDAL NEURONES

• PROJECTS• CORTICAL PYRAMIDAL NEURONES

• CORTICAL PYRAMIDAL NEURONES THUS UTILIZE GLUTAMATE TO COMMUNICATE BACK AND FORTH

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

• TYPICAL ANTIPSYCHOTICS

• PHENOTHIAZINES (CHLORPROMAZINE, PERPHENAZINE, FLUPHENAZINE, THIORIDAZINE ET AL)

• THIOXANTHENES (FLUPENTHIXOL, CLOPENTHIXOL)

• BUTYROPHENONES (HALOPERIDOL, DROPERIDOL)

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

• 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

• NIGROSTRIATAL PATHWAY• DYSTONIA

• AKATHISIA

• DRUG INDUCED PARKINSONISM

• TARDIVE DYSKINESIA

• TUBULOINFUNDIBULAR PATHWAY• GALACTORRHOEA

• SEXUAL DYSFUNCTION

• INFERTILITY

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

ANTIPSYCHOTIC USED

D2 BLOCKADEDECREASED DOPAMINE

DECREASED BLOCKING OF CHOLINERGIC

NEURONES

INCREASED ACETYLCHOLINE

EXTRAPYRAMIDAL SYMPTOMS

SO,

• MORE DOPAMINE = LESS ACETYLCHOLINE

• LESS DOPAMINE = MORE ACETYLCHOLINE

• LESS ACETYLCHOLINE = LESS EPS

• MORE ACETYLCHOLINE = MORE EPS

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

• 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.

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

• 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 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.

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.

• TREATMENT

• VIGOROUS TREATMENT WITH ANTIPARKINSONIAN DRUGS IS RECOMMENDED AS SOON AS POSSIBLE.

• MUSCLE RELAXANTS SUCH AS DIAZEPAM, DANTROLENE OR BROMOCRIPTINE MAY BE HELPFUL.

TYPICAL ANTIPSYCHOTICS

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

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

5HT1A INHIBITS CORTICAL PYRAMIDAL NEURONE

REGULATES HORMONES, COGNITION, ANXIETY, DEPRESSION

5HT2A EXCITES CORTICAL PYRAMIDAL NEURONESENHANCES GLUTAMATE RELEASE

SLEEP AND HALLUCINATIONREGULATION

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

• 5HT1A AND 5HT2A HAVE OPPOSITE ACTION IN REGULATING DOPAMINE RELEASE.

5HT1ASOMATODENDRITICAUTORECEPTORS

5HT1B/1D

5HT1B/1D TERMINAL AUTORECEPTORS

GABA

DA

DA

5HT2AXSEROTONIN

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

• 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 ?

DA NEURONEDA NEURONE OF NIGROSTRIATAL TRACT

5HT NEURONECAPSULE

SDA MOLECULESRELEASED

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

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

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

• 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

ACTIVATED BY 5HT

RELEASE OF GLUTAMATE

SEROTONIN

5HT2A

5HT1A5HT2A INHIBITOR

ACTIVATED BY 5HT

INHIBITION OF GLUTAMATE RELEASE

XX

3 NEURONE CIRCUIT MODEL

SEROTONERGIC NEURONES

GLUTAMINERGIC NEURONE

• 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

• 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)

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

• SEROTONIN PROMOTES PROLACTIN RELEASE BY STIMULATING 5HT2A RECEPTORS

SEROTONIN (5HT) STIMULATES PROLACTIN RELEASE FROM PITUITARYLACTOTROPH CELLS IN THE PITUITARY GLAND WHEN IT BINDS TO 5HT2A RECEPTORS. THUS, SEROTONIN AND DOPAMINE HAVE A RECIPROCAL REGULATORY ACTION ON PROLACTIN RELEASE.

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

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

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

• 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.

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.

• 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.

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.

• 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

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

GLUTAMATE AGONISTS OR ANTAGONISTS FOR TREATMENT OF PSYCHOSISNMDA 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

• 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

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.

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

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.

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.

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

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

• 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

• 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

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.

THANK YOU