French Antipsychotic 4-14-10 Presentation

7/27/2019 French Antipsychotic 4-14-10 Presentation

1/42


2/42

PSYCHOSIS#A syndrome of chronic disordered thinking and disturbed

behavior (schizophrenia, mania, depression)

Deficits in integrating thought and perception withemotion (some refer to a loss of cognitive control)

paranoid delusions/thought insertion/ideas of reference

hallucinations (generally auditory, but can be visual)loss of affect/poverty of speech/social withdrawal

impaired ability to function with others

idiopathic or organic etiology

Prevalence of schizophrenia: 1% of populationworldwide


3/42


4/42

MENTAL ILLNESSES

Environmental factors Maturational factors

Neuronal connectivity

Neurotransmitters Receptors/drug targets


5/42

Schizophrenia

Environmental Factors

Exposure to infections Toxic/Traumatic

( in utero) Insults

ALTERATIONS IN NEURODEVELOPMENT

Autoimmunity Stress during gestation or

early in childhood/adolescence


6/42

Maturational Processes

Apoptosis Synaptic Pruning Myelination (prenatal

to adolescence)

Unmasking Genetic Vulnerability


7/42

Neuronal Plasticity

Structural changes during development and in responseto environmental factors

Changes in neurotransmitter activity in response to

environmental factors

Neurotrophic factors and changes in gene transcription (eg. neuroregulin-1 which regulates neuronal migration)

Continues throughout life of the organism

Underlies learning and memory


8/42

NEURONAL CONNECTIVITY

Functional activity inneocortex ofschizophrenic patientsmay be decreased

Myelination Synaptic pruning

Hormonal effects ofpuberty

Exposure to stressors

Defective connections inmidbrain, nucleusaccumbens, thalamus,temporo-limbic andprefrontal cortex


9/42


10/42

STRUCTURAL BRAIN

CHANGES IN SCHIZOPHRENIA Schizophrenics show deficits

in tasks involving prefrontalcortex or those requiringworking memory

Prefrontal cortical thicknessis reduced 5-10%, neuron

size is down, but no changein neuron number

Synaptic connectivity isreduced

Medial dorsal thalamusshows 30% reduction inneuron number

Prefrontal cortex receivesfewer projections from thethalamus

Hippocampus shows altered

cytoarchitecture


11/42


12/42

The Dopamine HypothesisSchizophrenia results from excess activity of

dopamine neurotransmission because:

ALL antipsychotic drugs block dopamine

receptors.

Stimulant drugs which act through dopamine canproduce schizophrenic-like behaviors

(eg.amphetamines).

Levodopa, a dopamine precursor, can exacerbate

schizophrenic symptoms, or occasionally elicit them

in non-schizophrenic patients.

Higher levels of dopamine receptors measured in

brains of schizophrenics.

Brain [DA] increases during psychotic episodes but

not during remissions.


13/42


14/42

A HYPOTHESIS IN TRANSITION

All antipsychotic drugs which block dopamine receptors do not reverse allsymptoms

positives are more responsive

negatives may even be exacerbated

Antipsychotics blocking DA and 5-HT receptors seem better for both

positive and negative symptoms

NMDA glutamate--based on effects of PCP in humans

DA metabolites in CSF & plasma not significantly elevated in schizophrenics

Antipsychotic drugs block DA receptors immediately butantipsychotic benefits take several days to weeks to occur


15/42

New Findings

Polymorphism of COMT gene with increased activity and more

efficient metabolism of DA leading to:

lower than normal prefrontal cortex DA

release=hypofrontality

Polymorphism of-7 nAChR on chromosome 15 as cause of

disturbance in sensory gating=normalized by nicotine

Partial D-2 agonist and 5-HT-2/5-HT-1a antagonist effective for

positive/negative symptomatology


16/42

DOPAMINE RECEPTORS THE


17/42

DOPAMINE RECEPTORS: THE

HOLY GRAIL FOR

ANTIPSYCHOTIC MEDS?

Dopamine recognized as aneurotransmitter in the

1950s Five dopamine receptor

subtypes: D-1,-2,-3,-4,-5

Drug naive schizophrenicsshow elevated D2 receptornumber

Cortex has much higheramounts of D1 than D2receptors

chronic antipsychotic drugsdownregulate D1s in the

cortex and striatum


18/42

THE HOLY GRAIL FOR MEDS,CONTD

Striatum has high concentrations of D1 & D2receptors

All effective antipsychotics possess some threshold

level of D2 receptor blockade striatal D2s may be the site for antipsychotic drug-inducedmovement disorders

clozapine upregulates cortical D2s at doses that do notaffect striatal D2s

Limbic structures contain high concentrations of D4s clozapine has high affinity for D4s, but selective D4

antagonists fail to show antipsychotic efficacy

Serotonin inhibits dopamine neurotransmission atypicals show serotonin binding ability


19/42


20/42

DRUG TARGETS,

CONTD

The newer atypicals

have the ability to block

the behavioral effects of

phencyclidine (PCP)

PCP elicits behavioral/

cognitive symptoms

indistinguishable from

schizophrenia PCP is an uncompetitive

blocker of NMDA-

glutamate ion channel

function


21/42

NEUROTRANSMITTERS

Overactivity of dopamine in limbic regions

(positive symptoms?)

Abnormalities in dopamine storage, vesicular

transport, release or reuptake

NMDA-glutamate hypofunction (negative

symptoms?)


22/42


23/42

ANTIPSYCHOTIC DRUGS

no compound can target a given symptom

therapeutic effects correlated to potency at D-2

dopamine receptors

all have effects on other non-dopamine receptors (side-

effects, or therapeutic effects)

can also be used for Tourettes, control of acute mania,

intractable hiccups, choreas and ballisms


24/42

DRUG TARGETS

Dopamine receptors: D1, D2, D3, D4, D5

Serotonin receptors: 5-HT-1A, 2A, 3, 6, 7

Norepinephrine: -1 & -2

Muscarinic acetylcholine: mACh-1 & 4

Histamine: H-1 & 2

Dopamine, norepinephrine & serotonin

transporters

NMDA-glutamate receptor


25/42

DopamineReceptors

Occupancytherapeutic vs. sideeffects

At therapeutic doses the classical

antipsychotics occupy >75% of dopamineD-2 receptors.

85% occupancy needed to get

extrapyramidal side effects.

Clozapine, the atypical, blocks only 35%

D-2 receptors at therapeutic doses.


26/42


27/42

DRUG CLASSES

Phenothiazines: eg. chlorpromazine

Thioxanthenes

Butyrophenones: eg. haloperidol Diphenylbutylpiperidine

Dihydroindolone

Dibenzoxazepines: eg. clozapine Benzisoxazol: eg. risperidone


28/42

PHARMACOLOGICAL PROPERTIES

Neuroleptic syndrome:

suppression of spontaneous behavior

loss of initiative and interest (anhedonia)

loss of affect and emotional content

slowness of movement

Parkinson-like extrapyramidal effects

Unpleasant when given to non-psychotic

individual


29/42


30/42

TYPE MANIFESTATIONS MECHANISM

Autonomic nervous

system

Dry mouth, loss of

accommodation; difficultyurinating, constipation

Muscarinic blockade

Orthostatic hypotension,

impotence, failure to ejaculate

Alpha adrenergic

blockade

Central nervoussystem

Parkinsons syndrome; akathisia,dystonia

Dopamine receptorblockade

Tardive dyskinesia Dopamine receptor

supersensitivity

Toxic confusional state Muscarinic blockade

Endocrine system Galactorrhea; amenorrhea;

infertility, impotence

Hyperprolactinemia

secondary to dopamine

receptor blockade


31/42

Spectrum of Adverse Effects Caused by

Antipsychotic Drugs

Low PotencyFewer extrapyramidal reactions

(especially thioridazine)

More sedation, more postural

hypotensionGreater effect on the seizure

threshold, electrocardiogram(especially thioridazine)

More likely skin pigmentation andphotosensitivity

Occasional cases of cholestaticjaundice

Rare cases of agranulocytosis

High PotencyMore frequent extrapyramidal

reactions

Less sedation, less postural

hypotension

Less effect on the seizure

threshold, less cardiovascular

toxicity

Fewer anticholinergic effects

Occasional cases of neuroleptic

malignant syndrome


32/42


33/42


34/42

SIDE EFFECTS, contd.

Parkinsonian syndrome

neuroleptic malignant syndrome

akathisia acute dystonic reactions

tardivie dyskinesia


35/42

Comparison of Tardive Dystonia and

Tardive Dyskinesia

Tardive dystonia

Strikes younger

Strikes sooner in the course

of neuroleptic treatment

Poor prognosis

More males

Patients with mood disorders

may be more susceptibleAnticholinergics may improve

condition

Tardive dyskinesia

Strikes older

Strikes later in the course of

neuroleptic treatment

Variable prognosis

More females (?)


may be more susceptibleAnticholinergics usually

worsen condition


36/42

TABLE 6. Comparison of Tardive Dystonia and

Tardive Dyskinesia

Tardive dystonia

Strikes younger

Strikes sooner in the course

of neuroleptic treatment

Poor prognosis

More males


may be more susceptibleAnticholinergics may improve

condition

Tardive dyskinesia

Strikes older

Strikes later in the course of

neuroleptic treatment

Variable prognosis

More females (?)


may be more susceptibleAnticholinergics usually

worsen condition


37/42

SIDE EFFECTS

Autonomics--related to blockade of alpha-

adrenergic and muscarinic receptors

Endocrine effects, primarily prolactin

increases

Disruption of thermoregulatory control

Hypersensitivity reactions; eg.

agranulocytosis with clozapine; browning

of vision with thioridizine


38/42


39/42


40/42

Stress & Schizophrenia

Schizophrenic patients have alteredsensitivity to stressThey display abnormalities in autonomic nervous

system and hypothalmic-pituitary adrenal function inresponse to stress

Coping abilities seem best preserved inschizophrenics who suffer the least negativesymptoms

Cognitive deficits in schizophrenics may cause themto be less well adapted to their environment

Schizophrenics have difficulty filtering incomingsensory stimuli


41/42


42/42

Indications for Antipsychotic Drugs

Schizophrenia

Schizoaffective disorders

Acute control of mania

Tourettes syndrome

Huntingtons chorea and ballism

Intractable hiccups

Documents

French Antipsychotic 4-14-10 Presentation