Diseases of the nervous system Schizophrenia

Antipsychotics Psychoses – marked distortions of reality and disturbances in perception, intellectual functioning, affect (mood), motivation and motor behaviour psychoses e.g -affective disorders and schizophrenia Symptoms 1. Positive - delusions & hallucinations, disorganised speech, bizarre behaviour 2. Negative - loss or decrease of normal function:Complexity of symptoms in schizophreniaDiscrete, overlapping ‘component symptom complexes’ • Phenomenologically distinct, independent in course and onset • Pharmacologically distinguishableAetiology: genetic & environmental a developmental brain disorder -pregnancy/early childhood marijuana & cannabis predisposition - at least 10-20 genesStudies suggest that 4 people from every 1000 have, or have had an active psychotic disorder over the past year (annual prevalence)Cost of schizophrenia in England Societal cost £6.7 billion Treatment and care £2 billion (Typical) Antipsychotics Others resemble the phenothiazines of group 3: butyrophenones including: haloperidol (Dozic ®, Haldol ®, Serenace ®) Effectiveness of chlorpromazine in treating psychoses (USA) Resident patients in US institutions (Thousands) Year Example: Group 1 chlorpromazine (Largactil®) (Large number of compounds in groups 1, 2 and 3.) Phenothiazine derivatives Gross neuropathological changes & altered eg. metabolism, blood flow, chemistry Changes in the brain

Alterations in brain structure and blood flow in schizophreniaThe brain has larger ventriclesMany changes occur in schizophrenia brainsIn image 2 we can see altered brain blood flow in none medicated patientsHypoperfusion - frontal lobes, frontal cortex, anterior and medial cingulate gyri, parietal lobes (higher cognitive functions) Hyperperfusion - cerebellum, brainstem and thalamus Altered brain blood flow in schizophrenia (non-medicated patientsOver-activity of dopaminergic systems – particularly mesolimbic – associated with emotions and cognition

AntipsychoticsTypical Antipsychotics Phenothiazines derivatives (Large number of compounds in groups 1, 2 and 3.) Example: Group 1 chlorpromazine (Largactil®)Others resemble phenothiazines derivatives of group 3: butyrophenones including: haloperidol (Dozic ®, Haldol ®, Serenace ®))An expanding variety – include:clozapine (Clozaril ®, Denzapine ®, Zaponex ®) olanzapine (Zyprexa ®)These new line of drugs have an improved side effect profileNewly diagnosed – oral atypical antipsychotics first-line treatmentAntipsychotics – how do they work? Drugs are antagonists of various GPCRs eg. 5-HT BUT ALL ARE ANTAGONISTS OF DOPAMINE RECEPTORS – PARTICULARLY D2 RECEPTORS An example is clozapine but it has Multiple interactions Various 5-HT, dopamine, muscarinic acetylcholine, histamine and opioid receptors, adrenoceptors 5-HT and noradrenaline transportersInteractions with multiple targets is common – may be important for effectiveness, differences between drugs and possibly differences in effectiveness between patients. For example:-- Relative in-vitro binding of some antipsychotics.Remember – lower Ki = higher affinityA Common feature of antipsychotics – dopamine D2 receptor antagonistsSuggests schizophrenia due to over-activity of dopaminergic systemsPost-mortem studies show increased striatal D2 receptorsCause of illness or consequence of treatment? (Receptor up-regulation in response to antagonist?)Untreated schizophrenic patients have increased levels of striatal dopamine and D2 receptors

Experimental evidence higher number of receptors seen in schizophrenia AFTER DEPLETION OF DOPAMINED2 receptors - Gai -coupled reduce neural activity this may be due to mesocortical/striatal regions?There can be a therapeutic response but clinical efficacy can take weeks. This could be due to adaptationCurrent antipsychotics particularly effective on positive symptoms – suggests other problemsSome new developmentslutamate hypothesis of schizophrenia (SCZ) Reduced NMDA (N-methyl-D-aspartate) receptor function SCZ (evidence includes: phencyclidine/ketamine block NMDA-R & induce psychosis)Inhibit glycine uptake (to é synaptic levels) – studies with inhibitors of glycine transporter underwayalso evidence for glutamate Could glutamate be an effective therapy?Early clinical trials – as effective as olanzapine on +ve & -ve symptomsLY2140023 (pro-drug) LY404039 (agonist)Treatment options & effectiveness require improvement