PSYCHOSISPSYCHOSIS#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 referencehallucinations (generally auditory, but can be visual)loss of affect/poverty of speech/social withdrawalimpaired ability to function with othersidiopathic or organic etiology

Prevalence of schizophrenia: 1% of population worldwide

MENTAL ILLNESSESMENTAL ILLNESSES

Environmental factors Maturational factors Neuronal connectivity Neurotransmitters Receptors/drug targets

SchizophreniaSchizophrenia

Environmental Factors

Exposure to infections Toxic/Traumatic

( in utero) Insults

ALTERATIONS IN NEURODEVELOPMENT

Autoimmunity Stress during gestation or early in

childhood/adolescence

Maturational ProcessesMaturational Processes

Apoptosis Synaptic Pruning Myelination (prenatal to adolescence)

Unmasking Genetic Vulnerability

Neuronal PlasticityNeuronal 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

NEURONAL CONNECTIVITYNEURONAL 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

STRUCTURAL BRAIN STRUCTURAL BRAIN CHANGES IN SCHIZOPHRENIACHANGES 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

The Dopamine HypothesisThe Dopamine HypothesisSchizophrenia 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.

A HYPOTHESIS IN TRANSITIONA 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

New FindingsNew 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

DOPAMINE RECEPTORS: THE DOPAMINE RECEPTORS: THE HOLY GRAIL FOR HOLY GRAIL FOR

ANTIPSYCHOTIC MEDS?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

THE HOLY GRAIL FOR MEDS, THE HOLY GRAIL FOR MEDS, CONT’DCONT’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

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

NEUROTRANSMITTERSNEUROTRANSMITTERS

Overactivity of dopamine in limbic regions (positive symptoms?)Abnormalities in dopamine storage, vesicular

transport, release or reuptake

NMDA-glutamate hypofunction (negative symptoms?)

ANTIPSYCHOTIC DRUGSANTIPSYCHOTIC 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

DRUG TARGETSDRUG 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

DopamineDopamine ReceptorsReceptorsOccupancy—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.

DRUG CLASSESDRUG CLASSES

• Phenothiazines: eg. chlorpromazine

• Thioxanthenes

• Butyrophenones: eg. haloperidol

• Diphenylbutylpiperidine

• Dihydroindolone

• Dibenzoxazepines: eg. clozapine

• Benzisoxazol: eg. risperidone

PHARMACOLOGICAL PROPERTIESPHARMACOLOGICAL 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

TYPETYPE MANIFESTATIONS MANIFESTATIONS MECHANISM MECHANISM

Autonomic nervous system

Dry mouth, loss of accommodation; difficulty urinating, constipation

Muscarinic blockade

Orthostatic hypotension, impotence, failure to ejaculate

Alpha adrenergic blockade

Central nervous system

Parkinson’s syndrome; akathisia, dystonia

Dopamine receptor blockade

Tardive dyskinesia Dopamine receptor supersensitivity

Toxic confusional state Muscarinic blockade

Endocrine system Galactorrhea; amenorrhea; infertility, impotence

Hyperprolactinemia secondary to dopamine receptor blockade

Spectrum of Adverse Effects Caused by Spectrum of Adverse Effects Caused by Antipsychotic DrugsAntipsychotic Drugs

Low PotencyFewer extrapyramidal reactions

(especially thioridazine)More sedation, more postural

hypotensionGreater effect on the seizure

threshold, electrocardiogram (especially thioridazine)

More likely skin pigmentation and photosensitivity

Occasional cases of cholestatic jaundice

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

SIDE EFFECTS, cont’d.SIDE EFFECTS, cont’d.

• Parkinsonian syndrome

• neuroleptic malignant syndrome

• akathisia

• acute dystonic reactions

• tardivie dyskinesia

Comparison of Tardive Dystonia and Tardive Dyskinesia

Tardive dystoniaStrikes 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 dyskinesiaStrikes 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

Tardive dystoniaStrikes 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 dyskinesiaStrikes 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

SIDE EFFECTSSIDE 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

Stress & SchizophreniaStress & Schizophrenia

Schizophrenic patients have altered sensitivity to stressThey 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

Indications for Antipsychotic DrugsIndications for Antipsychotic Drugs

Schizophrenia

Schizoaffective disorders

Acute control of mania

Tourette’s syndrome

Huntington’s chorea and ballism

Intractable hiccups