What have we learned about treatment resistant schizohrenia and clozapine’s mode of action
R. Murray1, P. Morrison2
1Institute of Psychiatry, Psychology and Neuroscience, Psychiatry, London, United Kingdom, 2Argyle and Bute NHS Trust, Psychiatry, Lochgilphead, United Kingdom
Background: Whether there is more than one type of Treatment resistant schizophrenia remains unclear as does clozapine's mode of action
Aims & Objectives: 1) To establish if there are 2 types of treatment resistant schizophrenia (TRS)
2) To establish why clozapine is more effective than other antipsychotics for TRS
2) To establish why clozapine is more effective than other antipsychotics for TRS
Method: 1) Follow-up of two large samples of patients with their first episode of schizophrenia- AESOP and GAP.
2) Literature review of the pharmacology of clozapine
2) Literature review of the pharmacology of clozapine
Results: 1) In both FEP samples the majority of TRSpatients did not respond to antipsychotics from first onset. Such patients showed many characteristics of having been neurodevelopmentally impaired. However about 25% of TRS patients were insdistiunguishable from responders at onset but developed resistance later.
2) Patients with TRS show glutamate abnormalities, and clozapine has widespread effects on glutamate. However, these actions have not been proven to be different from those of other antipsychotics. Immune dysfunction is also reported in TRS, and clozapine has anti-inflammatory actions, but these have not been correlated with clinical improvement. Currently, there is a great deal of interest in muscarinic abnormalities in psychosis. Unlike most antipsychotics, clozapine has important effects on muscarinic receptors, particularly M1 and M4, and its major metabolite, N-desmethylclozapine, is a full agonist at M1. These effects are likely crucial to clozapine's effectiveness. In addition, clozapine's lower dopamine D2 receptor occupancy than other antipsychotics. Clozapine's multireceptor profile enables it to have beneficial actions on the nonpsychotic symptoms common in TRS; its ability to bind to histamine H1, serotonin 5-HT1A, and GABAB (gamma-aminobutyric acid B) receptors offers an explanation for its anxiolytic actions, while effects on 5-HT1A, 5-HT2A, and 5-HT7 receptors likely underlie its antidepressant properties. Clozapine shares these properties with olanzapine and quetiapine, but its affinity for muscarinic receptors may be the mechanism by which it is more effective in TRS.
2) Patients with TRS show glutamate abnormalities, and clozapine has widespread effects on glutamate. However, these actions have not been proven to be different from those of other antipsychotics. Immune dysfunction is also reported in TRS, and clozapine has anti-inflammatory actions, but these have not been correlated with clinical improvement. Currently, there is a great deal of interest in muscarinic abnormalities in psychosis. Unlike most antipsychotics, clozapine has important effects on muscarinic receptors, particularly M1 and M4, and its major metabolite, N-desmethylclozapine, is a full agonist at M1. These effects are likely crucial to clozapine's effectiveness. In addition, clozapine's lower dopamine D2 receptor occupancy than other antipsychotics. Clozapine's multireceptor profile enables it to have beneficial actions on the nonpsychotic symptoms common in TRS; its ability to bind to histamine H1, serotonin 5-HT1A, and GABAB (gamma-aminobutyric acid B) receptors offers an explanation for its anxiolytic actions, while effects on 5-HT1A, 5-HT2A, and 5-HT7 receptors likely underlie its antidepressant properties. Clozapine shares these properties with olanzapine and quetiapine, but its affinity for muscarinic receptors may be the mechanism by which it is more effective in TRS.
Discussion & Conclusions: There are two types of Treatment resistant schizophenia. It is most likely that clozapine's muscarinic effects decrease striatal dopamine sufficiently for its lower D2 receptor occupancy to reduce dopamine signalling sufficiently to reduce psychotic symptoms without the usual side-effects associated with D2 blockade. Whether there are differential effects on the two types of TRS remains to be established.
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