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PSYCHOSIS. # A syndrome of chronic disordered thinking and disturbed behavior (schizophrenia, mania, depression) Deficits in integrating thought and perception with emotion (some refer to a loss of “cognitive control”)  paranoid delusions/thought insertion/ideas of reference

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PSYCHOSIS

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PSYCHOSIS

#A syndrome of chronic disordered thinking and disturbed behavior (schizophrenia, mania, depression)

  • Deficits in integrating thought and perception with emotion (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 population worldwide


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MENTAL ILLNESSES

  • Environmental factors

  • Maturational factors

  • Neuronal connectivity

  • Neurotransmitters

  • Receptors/drug targets


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Schizophrenia

Environmental Factors

Exposure to infections Toxic/Traumatic ( in utero)Insults

ALTERATIONS IN NEURODEVELOPMENT

AutoimmunityStress during gestation or early in childhood/adolescence


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Maturational Processes

Apoptosis Synaptic Pruning Myelination (prenatal to adolescence)

Unmasking Genetic Vulnerability


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Neuronal Plasticity

  • Structural changes during development and in response to 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


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NEURONAL CONNECTIVITY

  • Functional activity in neocortex of schizophrenic patients may be decreased

    • Myelination

    • Synaptic pruning

    • Hormonal effects of puberty

    • Exposure to stressors

    • Defective connections in midbrain, nucleus accumbens, thalamus, temporo-limbic and prefrontal cortex


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STRUCTURAL BRAIN CHANGES IN SCHIZOPHRENIA

  • Schizophrenics show deficits in tasks involving prefrontal cortex or those requiring working memory

  • Prefrontal cortical thickness is reduced 5-10%, neuron size is down, but no change in neuron number

  • Synaptic connectivity is reduced

  • Medial dorsal thalamus shows 30% reduction in neuron number

  • Prefrontal cortex receives fewer projections from the thalamus

  • Hippocampus shows altered cytoarchitecture


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The Dopamine Hypothesis

  • Schizophrenia results from excess activity of dopamine neurotransmission because:

    • ALL antipsychotic drugs block dopamine receptors.

    • Stimulant drugs which act through dopamine can produce 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.


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A HYPOTHESIS IN TRANSITION

  • All antipsychotic drugs which block dopamine receptors do not reverse all symptoms

    • 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 but antipsychotic benefits take several days to weeks to occur


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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


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DOPAMINE RECEPTORS: THE HOLY GRAIL FOR ANTIPSYCHOTIC MEDS?

  • Dopamine recognized as a neurotransmitter in the 1950’s

  • Five dopamine receptor subtypes: D-1,-2,-3,-4,-5

  • Drug naive schizophrenics show elevated D2 receptor number

  • Cortex has much higher amounts of D1 than D2 receptors

    • chronic antipsychotic drugs downregulate D1’s in the cortex and striatum


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THE HOLY GRAIL FOR MEDS, CONT’D

  • Striatum has high concentrations of D1 & D2 receptors

  • All effective antipsychotics possess some threshold level of D2 receptor blockade

    • striatal D2s may be the site for antipsychotic drug-induced movement disorders

    • clozapine upregulates cortical D2s at doses that do not affect 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


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DRUG TARGETS,CONT’D

  • 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


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NEUROTRANSMITTERS

  • Overactivity of dopamine in limbic regions (positive symptoms?)

    • Abnormalities in dopamine storage, vesicular transport, release or reuptake

  • NMDA-glutamate hypofunction (negative symptoms?)


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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 Tourette’s, control of acute mania, intractable hiccups, choreas and ballisms


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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


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DopamineReceptors

Occupancy—therapeutic vs. side effects

At therapeutic doses the “classical” antipsychotics occupy >75% of dopamine D-2 receptors.

85% occupancy needed to get extrapyramidal side effects.

Clozapine, the “atypical”, blocks only 35% D-2 receptors at therapeutic doses.


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DRUG CLASSES

  • Phenothiazines: eg. chlorpromazine

  • Thioxanthenes

  • Butyrophenones: eg. haloperidol

  • Diphenylbutylpiperidine

  • Dihydroindolone

  • Dibenzoxazepines: eg. clozapine

  • Benzisoxazol: eg. risperidone


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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


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TYPE MANIFESTATIONS MECHANISM


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Low Potency

Fewer extrapyramidal reactions (especially thioridazine)

More sedation, more postural hypotension

Greater effect on the seizure threshold, electrocardiogram (especially thioridazine)

More likely skin pigmentation and photosensitivity

Occasional cases of cholestatic jaundice

Rare cases of agranulocytosis

High Potency

More 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

Spectrum of Adverse Effects Caused by Antipsychotic Drugs


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SIDE EFFECTS, cont’d.

  • Parkinsonian syndrome

  • neuroleptic malignant syndrome

  • akathisia

  • acute dystonic reactions

  • tardivie dyskinesia


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Tardive dystonia

Strikes younger

Strikes sooner in the course of neuroleptic treatment

Poor prognosis

More males

Patients with mood disorders may be more susceptible

Anticholinergics may improve condition

Tardive dyskinesia

Strikes older

Strikes later in the course of neuroleptic treatment

Variable prognosis

More females (?)

Patients with mood disorders may be more susceptible

Anticholinergics usually worsen condition

Comparison of Tardive Dystonia and Tardive Dyskinesia


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Tardive dystonia

Strikes younger

Strikes sooner in the course of neuroleptic treatment

Poor prognosis

More males

Patients with mood disorders may be more susceptible

Anticholinergics may improve condition

Tardive dyskinesia

Strikes older

Strikes later in the course of neuroleptic treatment

Variable prognosis

More females (?)

Patients with mood disorders may be more susceptible

Anticholinergics usually worsen condition

TABLE 6. Comparison of Tardive Dystonia and Tardive Dyskinesia


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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


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Stress & Schizophrenia

Schizophrenic patients have altered sensitivity to stress

  • They display abnormalities in autonomic nervous system and hypothalmic-pituitary adrenal function in response to stress

  • Coping abilities seem best preserved in schizophrenics who suffer the least negative symptoms

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

  • Schizophrenics have difficulty filtering incoming sensory stimuli


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Indications for Antipsychotic Drugs

Schizophrenia

Schizoaffective disorders

Acute control of mania

Tourette’s syndrome

Huntington’s chorea and ballism

Intractable hiccups


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