Schizophrenia and Neuroleptics

Outline
• • • • • • Definitions The nature of schizophrenia Dopamine hypothesis of schizophrenia 5-HT hypothesis of schizophrenia Typical neuroleptics Atypical neuroleptics

Neuroses vs Psychoses
Neurosis – Anxiety state; phobia; hypochondria Psychoses:• Schizophrenia – Positive and negative symptoms • Affective disorders (eg depression, mania) • Organic psychoses (caused by eg head injury, alcoholism etc)

Schizophrenia
• Affects around 1% of the population • Often begins in adolescence/young adult • Relapses and remission, or chronic and progressive • Genetic and environmental factors • Possibly a neurodevelopmental disorder

Schizophrenia - Symptoms
A: Positive symptoms • Delusions • Hallucinations • Thought disorder Neuroleptic drugs effective B: Negative symptoms • Withdrawal • Flattening of emotional responses • Dementia Neuroleptic drugs less effective

Drug treatment of schizophrenia
Antischizophrenic drugs can be known as any of the following:• Antipsychotic drugs • Neuroleptic drugs • Major tranquillisers

Dopamine Hypothesis
1. All anti-psychotic drugs are anti-DA 2. Chronic amphetamine 3. Chronic L-DOPA 4. psychosis psychosis

DA concentration in L. amygdala

Correlation between the clinical potency and affinity for dopamine D2 receptors among antipsychotic drugs. Clinical potency is expressed as the daily dose used in treating schizophrenia, and binding activity is expressed as the concentration needed to produce 50% inhibition of haloperidol binding. (From Seeman P et al. 1976 Nature 361: 717.)

DA Hypothesis
5. DA receptor no. in schizophrenic brain [??] – conflicting results
D4 receptors 6-fold, but selective D4 antagonist L745870 ineffective

6. Overactivity of DA neurones to limbic region and prefrontal cortex

5-HT Hypothesis
1. LSD is a 5-HT analogue and causes hallucinations and delusions

2. Dimethyltryptamine hallucinations, and occurs in the urine of schizophrenics 3. Some newer antipsychotic drugs are antagonists at 5-HT2A receptors

Graph showing the binding of ziprasidone to both 5-HT2 and D 2 receptors. (from Mamo et al (2004), Am J Psychiatry 161, 818-825)

Classes of antipsychotic drugs
1. Typical (“classical”) antipsychotics:chlorpromazine, haloperidol, fluphenazine, thioridazine, flupenthixol

2. Atypical antipsychotics:clozapine, risperidone, sulpiride, olanzapine

Also see Rang, Dale, Ritter & Flower (6th edition, 2007), Table 38.1

Typical Neuroleptics
• • • • • • “classical” antipsychotics; pre-1980 Promethazine surgery-induced stress All have similar properties Extrapyramidal side effects (EPS) Little effect on negative symptoms Phenothiazines also block histamine, catecholamine, acetylcholine and 5-HT receptors

Extrapyramidal side effects
• From D2 receptor block

1. Acute dystonias
2. Tardive dyskinesia

Acute dystonias
• involuntary movements (muscle spasms, protruding tongue, etc), Parkinson-like syndrome • decline over time; reversible when treatment stops • Consistent with block of nigrostriatal pathway

Tardive dyskinesia
• Months/years; affects 20-40% of patients using classical drugs • Involuntary movements of face, tongue, trunk and limbs • Disabling, often irreversible, worsens when treatment stops

Other Side Effects
• H1 block:- sedation; anti-emetic (eg phenothiazines) • Muscarinic block:- blurred vision, increased iop, dry mouth and eyes, constipation, urinary retention  a-adrenoceptors:- hypotension • Also jaundice, leukopenia, agranulocytosis

Atypical Neuroleptics
• Newer compounds, more varied effects • Effective in treatment-resistant patients, and negative symptoms • Clozapine lacks EPS and affects only ventral tegmental neurones, not those in substantia nigra. • More selective for mesolimbic/ mesocortical pathway

“ATYPICAL” NEUROLEPTICS

DRUG clozapine olanzapine risperidone amisulpride

RECEPTORS BLOCKED D4 > D2 D4 > D2 5HT2 > D2 D2 /D3 >> D4

ADVERSE REACTIONS blood dyscrasia no dyscrasia various CNS

Outline
• • • • • • Definitions The nature of schizophrenia Dopamine hypothesis of schizophrenia 5-HT hypothesis of schizophrenia Typical neuroleptics Atypical neuroleptics

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