#A syndrome of chronic disordered thinking and disturbed

PSYCHOSIS

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

MENTAL ILLNESSES
Environmental factors Maturational factors Neuronal connectivity Neurotransmitters Receptors/drug targets

Schizophrenia
Environmental Factors
Exposure to infections ( in utero) Toxic/Traumatic Insults

ALTERATIONS IN NEURODEVELOPMENT

Autoimmunity

Stress during gestation or early in childhood/adolescence

Maturational Processes

Apoptosis

Synaptic Pruning Myelination (prenatal to adolescence)

Unmasking Genetic Vulnerability

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

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

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

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.

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

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

DOPAMINE RECEPTORS: THE HOLY GRAIL FOR ANTIPSYCHOTIC MEDS?

Dopamine recognized as a neurotransmitter in the 1950s 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 D1s in the cortex and striatum

THE HOLY GRAIL FOR MEDS,

CONTD
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, 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 NMDAglutamate ion channel function

NEUROTRANSMITTERS
Overactivity of dopamine in limbic regions (positive symptoms?)
Abnormalities in dopamine storage, vesicular transport, release or reuptake

NMDA-glutamate hypofunction (negative symptoms?)

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 (sideeffects, or therapeutic effects)

can also be used for Tourettes, control of acute mania, intractable hiccups, choreas and ballisms

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

Dopamine Receptors
Occupancytherapeutic 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 CLASSES
Phenothiazines: eg. chlorpromazine Thioxanthenes Butyrophenones: eg. haloperidol Diphenylbutylpiperidine Dihydroindolone Dibenzoxazepines: eg. clozapine Benzisoxazol: eg. risperidone

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

TYPE
Autonomic nervous system

MANIFESTATIONS
Dry mouth, loss of accommodation; difficulty urinating, constipation Orthostatic hypotension, impotence, failure to ejaculate

MECHANISM
Muscarinic blockade

Alpha adrenergic blockade Dopamine receptor blockade Dopamine receptor supersensitivity Muscarinic blockade Hyperprolactinemia secondary to dopamine receptor blockade

Central nervous system

Parkinsons syndrome; akathisia, dystonia Tardive dyskinesia

Toxic confusional state Endocrine system Galactorrhea; amenorrhea; infertility, impotence

Spectrum of Adverse Effects Caused by Antipsychotic Drugs

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

SIDE EFFECTS, contd.

Parkinsonian syndrome neuroleptic malignant syndrome akathisia acute dystonic reactions tardivie dyskinesia

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 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 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

SIDE EFFECTS
Autonomics--related to blockade of alphaadrenergic and muscarinic receptors Endocrine effects, primarily prolactin increases Disruption of thermoregulatory control Hypersensitivity reactions; eg. agranulocytosis with clozapine; browning of vision with thioridizine

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

Indications for Antipsychotic Drugs

Schizophrenia Schizoaffective disorders Acute control of mania Tourettes syndrome Huntingtons chorea and ballism Intractable hiccups