Lyn S. Pilowsky

Glutamate and dopamine dysregulation in schizophrenia - a synthesis and selective review

The dopamine hypothesis of schizophrenia is the principal explanatory model of antipsychotic drug action. Recent discoveries extend our understanding of the neurochemistry of schizophrenia, with increasing evidence of dysfunction in glutamate and GABA as well as dopamine systems. In this review, we study the evidence for dopaminergic dysfunction in schizophrenia, drawing data from neurochemical imaging studies. We also review the NMDA receptor hypofunction hypothesis of schizophrenia as a supplementary explanatory model for the illness. We examine predictions made by the NMDA receptor hypofunction hypothesis and consider how they fit with current neurochemical findings in patients and animal models. We consider the case for glutamatergic excitotoxicity as a key process in the development and progression of schizophrenia, and suggest ways in which glutamate and dopamine dysregulation may interact in the condition.

First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients.

First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients

Latent inhibition in drug naive schizophrenics: relationship to duration of illness and dopamine D2 binding using SPET

The dual aims of the study were (1) to examine the effect of neuroleptic medication on the expression of latent inhibition (LI) by studying LI in drug naive schizophrenic patients, and (2) to investigate the relationship between LI and dopamine D2 receptor binding in the basal ganglia using single photon emission tomography (SPET). Subjects constituted a sub-set of patients investigated in a major study of in vivo D2 receptor binding in schizophrenia (Pilowsky et al., 1993). Striatal D2 receptor binding was assessed in 15 neuroleptic naive schizophrenic patients and 13 healthy volunteers. The performance of subjects on a within-subject auditory latent inhibition paradigm was also assessed. There was found to be no significant difference in LI between schizophrenic patients and normal controls, both groups showing a strong within-subject LI effect. There was also found to be no association between LI and dopamine D2 receptor binding in either the left or the right basal ganglia. This lack of association indicates that LI is not directly related to post-synaptic D2 receptor levels in the striatum. LI was, however, found to be correlated with duration of illness in the schizophrenic group. Patients with a relatively short duration of illness (< 12 months) tended to show reversed, or absent, LI whereas patients with a longer illness duration (> 12 months) showed intact LI. The effect on LI of duration of illness is consistent with previous findings that LI is disrupted specifically in acute, but not chronic, schizophrenia. Previous studies have assumed that this pattern of results is due to the stabilising effect of long-term neuroleptic medication. The present findings in a sample of neuroleptic naive schizophrenic patients indicate that this is unlikely to be the case. Rather, it appears that the reinstatement of LI in schizophrenic patients over time is due to a factor(s) intrinsic to the evolution of the schizophrenic illness.

Clozapine, single photon emission tomography, and the D2 dopamine receptor blockade hypothesis of schizophrenia

According to the dopamine hypothesis of schizophrenia, D2 receptor blockade is essential for a drug to have antipsychotic potency, and antipsychotic potency and D2 blockade are linearly related in vitro. To test this assumption in vivo, we have compared clinical response with central D2 dopamine receptor availability measured by 123I-iodobenzamide single photon emission tomography in two groups of schizophrenic patients. 6 patients were on typical antipsychotic drugs and 10 were on the atypical antipsychotic clozapine, including 2 patients from the first group. The patients on typical antipsychotics showed poor therapeutic response despite D2 receptor blockade. Significant clinical improvement occurred in all patients on clozapine, but at a lower level of D2 blockade by the drug. These findings suggest a more complex relation between D2 blockade and clinical efficacy than was previously thought.

Limbic selectivity of clozapine

6motile sperm cells per mL, the inclusion criterion for the use of ICSI in the Netherlands. Both oligozoospermic (n=69) and azoospermic (n=11) men were included. All patients were karyotyped, and a consecutive subgroup (n=58) was also tested for Y-chromosomal deletions and CFTR mutations. We found an abnormal karyotype in peripheral blood lymphocytes in seven (8·8%) of 80 patients, ten-fold more than the overall population incidence of 0·85% 2 (p<0·001, 2 test; table). We analysed Y-chromosomal deletions with a multiplex PCR system with markers for the AZF-a, AZF-b, and AZF-c regions. 3 With markers sY254 and sY255, three (5%) of 58 patients were found to have an AZF-c deletion associated with the deleted-in-azoospermia (DAZ) gene. No AZF deletions were detected with this assay in a study of 100 fertile male controls. 3

Schizophrenia: A Neurodevelopmental Perspective

The role of aberrant neurodevelopment in the etiology of schizophrenia is reviewed in light of recent nueropathologic, neurochemical, and neuroimaging evidence of cerebral abnormalities in schizophrenic patients. There may exist some genetic defect in the control of brain development. Clinical epidemiologic surveys highlight the importance of obstetric amplications, and prenatal exposure to influenza epidemics in contributing to these abnormalities. It is suggested that such environmental hazards and aberrations in the control of early brain development produce the neuronal phenotype that manifests as schizophrenia with early age of onset of symptoms associated with soft neurologic signs and is more common in young males.

The place of partial agonism in psychiatry: recent developments

Drugs used to treat psychiatric disorders, although effective, are often restricted by adverse events. The use of partial agonists for treating hypertension was found to limit some of the side-effects in some patients. This led to the investigation of partial agonists as a treatment modality in psychiatric disorders. Partial agonists have a lower intrinsic efficacy than full agonists leading to reduced maximum response. They can act as antagonists by competing for receptor binding with full agonists. The level of activity depends on the level of endogenous receptor activity. Buprenorphine, a partial agonist at the mu-opioid receptor, is used to treat patients with addiction and decreases the symptoms of withdrawal and risks of overdose and intoxication. The anxiolytic buspirone shows partial agonism at 5-HT1A receptors, and this seems to provide anxioselective effects, without inducing extrapyramidal side-effects, convulsions, tolerance or withdrawal reactions. In schizophrenia, partial dopamine agonism results in antagonistic effects at sites activated by high concentrations of dopamine and agonistic effects at sites activated by low concentrations of dopamine. This stabilizes the dopamine system to effect antipsychotic action without inducing adverse motor or hormonal events. Aripiprazole is the first ‘dopamine system stabilizer’, and the data are promising, with efficacy at least equivalent to that with current atypical antipsychotics but fewer of the troublesome side-effects. Partial agonists seem to provide a way to fine-tune the treatment of psychiatric disorders by maximizing the treatment effect while minimizing undesirable adverse events.

Semantic organization and verbal memory efficiency in patients with schizophrenia

The role of semantic organization in verbal memory efficiency in schizophrenia was investigated. Patients and healthy controls were administered a free-recall task involving 1 nonsemantically organizable list, 1 list organizable in semantic categories with typical instances, and 1 list organizable in semantic categories with atypical instances. Reduced semantic organization was observed in patients. Regression analyses showed that the semantic clustering score in the atypical organizable list made a significant contribution to recall performance in patients. When semantic clustering was controlled, the effect of diagnosis on free recall was significant. These results suggest that depth of semantic organization is a crucial factor of verbal memory performance in schizophrenia. However, semantic organizational deficit does not account for the whole recall impairment.

Optimizing limbic selective D2/D3 receptor occupancy by risperidone: a [123I]-epidepride SPET study.

Selective action at limbic cortical dopamine D2-like receptors is a putative mechanism of atypical antipsychotic efficacy with few extrapyramidal side effects. Although risperidone is an atypical antipsychotic with high affinity for D2 receptors, low-dose risperidone treatment is effective without inducing extrapyramidal symptoms. The objective was to test the hypothesis that treatment with low-dose risperidone results in ‘limbic selective’ D2/D3 receptor blockade in vivo. Dynamic single photon emission tomography (SPET) sequences were obtained over 5 hours after injection of [123I]-epidepride (∼150 MBq), using a high-resolution triple-headed brain scanner (Marconi Prism 3000XP). Kinetic modelling was performed using the simplified reference region model to obtain binding potential values. Estimates of receptor occupancy were made relative to a normal volunteer control group (n = 5). Six patients treated with low-dose risperidone (mean = 2.6 mg) showed moderate levels of D2/D3 occupancy in striatum (49.9%), but higher levels of D2/D3 occupancy in thalamus (70.8%) and temporal cortex (75.2%). Occupancy values in striatum were significantly different from thalamus (F (1,4) = 26.3, p < 0.01) and from temporal cortex (F (1,4) = 53.4, p < 0.01). This is the first study to evaluate striatal and extrastriatal occupancy of risperidone. Low dose treatment with risperidone achieves a similar selectivity of limbic cortical over striatal D2/D3 receptor blockade to that of atypical antipsychotics with lower D2/D3 affinity such as clozapine, olanzapine and quetiapine. This finding is consistent with the relevance of ‘limbic selective’ D2/D3 receptor occupancy to the therapeutic efficacy of atypical antipsychotic drugs.

Does intravenous Δ9-tetrahydrocannabinol increase dopamine release? A SPET study.

Intravenous (IV) Δ9-tetrahydrocannabinol (THC) induces transient psychotic symptoms in healthy subjects and in schizophrenic patients, but the psychotomimetic mechanism is unknown. One possibility is that THC stimulates dopamine (DA) release in the striatum. In this study we tested whether IV THC led to an increase in striatal DA release compared to placebo. We also investigated whether DA release and positive psychotic symptoms were related. Eleven healthy male volunteers completed two 123I-iodobenzamide ([123I]IBZM) single photon emission tomography (SPET) sessions and received IV THC (2.5 mg) or placebo in a randomized counterbalanced order, under double-blind conditions. Analysable data were obtained from nine participants. The Positive and Negative Syndrome Scale (PANSS) was used to rate psychotomimetic effects. Striatal binding index values were calculated using the occipital cortex as a reference region. Both the PANSS positive and general symptoms increased significantly at 30 min following IV THC. There were no significant differences in binding index in the caudate or putamen under THC compared to placebo conditions. Positive psychotic symptoms and DA release were unrelated. THC did not lead to a significant increase in DA release even though the dose was sufficient for participants to have psychotic symptoms. These findings do not support a central role for striatal DA in THC-elicited psychosis.