Hallucinations and two types of free-recall intrusion in schizophrenia.

BACKGROUND: Previous research has demonstrated that various types of verbal source memory error are associated with positive symptoms in patients with schizophrenia. Notably, intrusions in free recall have been associated with hallucinations and delusions. We tested the hypothesis that extra-list intrusions, assumed to arise from poor monitoring of internally generated words, are associated with verbal hallucinations and that intra-list intrusions are associated with global hallucination scores. METHOD: A sample of 41 patients with schizophrenia was administered four lists of words, followed by free recall. The number of correctly recalled words and the number of extra- and intra-list intrusions were tallied. RESULTS: The verbal hallucination score was significantly correlated with the number of extra-list intrusions, whereas it was unrelated to the number of correctly recalled words. The number of intra-list intrusions was significantly correlated with the global, but not with the verbal, hallucination score in the subsample of hallucinating patients. It was marginally significantly correlated with the delusion score in delusional patients. CONCLUSIONS: The data corroborate the view that verbal hallucinations are linked to defective monitoring of internal speech, and that errors in context processing are involved in hallucinations and delusions.

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-HT(1A) 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.

Cognitive functioning and GABAA/benzodiazepine receptor binding in schizophrenia: a 123I-iomazenil SPET study.

BACKGROUND: The role of the inhibitory neurotransmitter gamma aminobutyric acid (GABA) in schizophrenia has previously been investigated using postmortem material. Recently, using single photon emission tomography (SPET) with the selective benzodiazepine antagonist 123I-Iomazenil as the radioligand, we have demonstrated an in vivo relationship between reduced GABAA/benzodiazepine receptor binding and the severity of positive symptomatology in schizophrenia. The present study aimed to build on this using the same in vivo scanning techniques, and relating findings to cognitive functioning. METHODS: Ten nonpsychiatric control subjects and 15 schizophrenic patients, matched for age and handedness, were scanned. A battery of neuropsychologic tests was also administered. RESULTS: Correlational analysis revealed a pattern of increased correlations between GABAA/benzodiazepine receptor binding and task performance, in the schizophrenic group compared to the control group. CONCLUSIONS: Findings are preliminary but suggest a relationship between reduced GABAA/benzodiazepine receptor binding and poorer cognitive functioning, involving memory and visual attention processes, in the schizophrenic group but not in the control group. A role for GABA in the pathophysiology of schizophrenia is suggested. Limitations of the present study and suggestions for future research are discussed.

Correlation between reduced in vivo benzodiazepine receptor binding and severity of psychotic symptoms in schizophrenia.

OBJECTIVE: Although there is evidence from postmortem studies suggestive of deficient inhibitory neurotransmission of gamma-aminobutyric acid (GABA) in schizophrenia, no direct in vivo evidence has been obtained to date. The authors used single photon emission computed tomography (SPECT) with iodine-123-labeled iomazenil ([123I]iomazenil), a radioligand that selectively binds with high affinity to the benzodiazepine subunit of the GABAA receptor complex in the human brain, to investigate the presence of benzodiazepine receptor abnormalities in the cerebral cortex of living subjects with schizophrenia. METHOD: Dynamic [123I]iomazenil SPECT was performed in 15 patients (14 patients with DSM-III-R schizophrenia and one with schizophreniform disorder) and 12 healthy subjects over a period of 2 hours. The time-integral method was used to generate ratios of "specific" to "nonspecific" [123I]iomazenil binding at equilibrium for several cortical regions. RESULTS: No overall between-group differences in benzodiazepine receptor binding were found, but significant correlations emerged between the severity of schizophrenic symptoms and [123I]iomazenil binding in limbic cortical regions: positive symptom scores were negatively correlated with benzodiazepine receptor binding in the left medial temporal region, and negative symptoms were inversely related to receptor binding in the medial frontal region. These correlations were not significant when a Bonferroni correction for multiple comparisons was applied. CONCLUSIONS: These preliminary results are consistent with previous research implicating limbic cortical regions in the pathophysiology of schizophrenia, suggesting that reduced inhibitory GABAergic tone in these areas may contribute to the appearance of schizophrenic symptoms.

Schizophrenia: a neurodevelopmental perspective.

The role of aberrant neurodevelopment in the etiology of schizophrenia is reviewed in light of recent neuropathologic, 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 complications, 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.

Dopamine D2 receptor blockade in vivo with the novel antipsychotics risperidone and remoxipride--an 123I-IBZM single photon emission tomography (SPET) study.

Risperidone and remoxipride are recently introduced atypical antipsychotics, with clinical efficacy comparable to that of classical antipsychotics but lower propensity to induce extrapyramidal side effects (EPS). It is unclear whether these properties relate to weak dopamine D2 receptor blockade in vivo, as has been suggested for the archetypal atypical antipsychotic clozapine. We have used 123I-IBZM single photon emission tomography (SPET) to characterize the patterns of striatal D2 receptor binding in vivo in DSMIII-R-diagnosed schizophrenic and schizo-affective patients treated with either risperidone (n = 6) or remoxipride (n = 4) but predominantly EPS free. These groups were compared to age- and BPRS- matched subjects from a previously reported D2 receptor binding database of patients treated with clozapine (n = 10) and classical antipsychotics (n = 10). Patients on risperidone and remoxipride had high levels of D2 receptor blockade, comparable to those of patients on classical antipsychotics, and significantly greater than those obtained with clozapine-treated patients (risperidone versus clozapine, P < 0.005; remoxipride versus clozapine, P < 0.025). These results suggest high levels of striatal D2 receptor occupancy in association with remoxipride and risperidone treatment and argue against modest D2 antagonism as the explanation for the low incidence of EPS associated with these drugs.

In vivo effects on striatal dopamine D2 receptor binding by the novel atypical antipsychotic drug sertindole--a 123I IBZM single photon emission tomography (SPET) study.

The novel antipsychotic drug sertindole has an atypical pharmacological profile. We have estimated striatal D2 dopamine binding in schizophrenic patients treated with sertindole using 123I iodobenzamide (IBZM) SPET. Patients were recruited from a clinical trial of sertindole's tolerability and efficacy. Striatal D2 binding in sertindole-treated patients (n = 5), was compared with previously reported data from clozapine (n = 10); olanzapine (n = 6); typical antipsychotic responsive (n = 10); and risperidone (n = 6)-treated groups. Mean PANSS (structured clinical interview for the positive and negative syndrome scale) scores showed clinical improvement in the sertindole group. Few extrapyramidal side effects (EPS) were recorded [average Simpson-Angus (SAS) score = 2.6]. Sertindole-treated patients had mean D2 binding indices (+/-SE) significantly lower than clozapine-treated patients (1.19 +/- 0.04) versus (1.49 +/- 0.04), and olanzapine-treated patients (1.41 +/- 0.06); and similar to those of risperidone (1.24 +/- 0.04) and typical antipsychotic responsive (1.25 +/- 0.05) treated patients. In this patient sample the preliminary evidence suggests that sertindole's decreased tendency to induce EPS at clinically therapeutic doses is not due to limited occupancy of striatal D2 receptors in vivo, and as is the case for risperidone, patients are protected from EPS by some other intrinsic effect of the drug.

Dopamine D2 receptor occupancy in vivo by the novel atypical antipsychotic olanzapine--a 123I IBZM single photon emission tomography (SPET) study.

We have studied striatal D2 dopamine binding in schizophrenic patients treated with the novel atypical antipsychotic drug, olanzapine. 123I iodobenzamide (IBZM) single photon emission tomography (SPET) was used to estimate striatal dopamine D2 receptor binding in vivo. Patients were recruited from a prospective, double blind controlled trial of olanzapine versus haloperidol treatment. In vivo striatal D2 binding data from olanzapine treated patients (n = 6) were compared with previously reported data from typical antipsychotic responsive (n = 10); clozapine (n = 10); and risperidone (n = 6) treated patient groups. Mean % Brief Psychiatric Rating Scale score (BPRS) improvement following olanzapine treatment was 49% (SD 44). The hypothesis that clinical improvement in olanzapine treated patients would be associated with higher mean striatal D2 binding of 123I IBZM (reflecting lower levels of D2 occupancy) than typical antipsychotic (1.25 +/- 0.05) or risperidone (1.24 +/- 0.04) treatment was confirmed. Olanzapine treated patients had similar levels of striatal D2 binding in vivo (1.41 +/- 0.06) as those treated with clozapine (1.49 +/- 0.04). This preliminary evidence suggests olanzapine is another atypical antipsychotic drug in which therapeutic response is not associated with a high degree of striatal D2 receptor occupancy in vivo.

Striatal and temporal cortical D2/D3 receptor occupancy by olanzapine and sertindole in vivo: a [123I]epidepride single photon emission tomography (SPET) study.

RATIONALE: Previous work suggests clozapine preferentially targets limbic cortical dopamine systems, which could help account for its lack of extrapyramidal side effects (EPS) and superior therapeutic efficacy. OBJECTIVES: To test the hypothesis that olanzapine, a novel atypical antipsychotic drug, occupies temporal cortical D2/D3 receptors to a greater extent than striatal D2/D3 receptors in vivo. METHODS: Nine schizophrenic patients taking either olanzapine [(n=5; mean (SD) age: 32.5 (6.5) years; daily dose: 18.3 (2.6) mg] or sertindole [(n=4; mean (SD) age: 30.3 (7.4) years; daily dose: 16 (5.6) mg] were studied with [123I]epidepride ((S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxybenz amide) and single photon emission tomography (SPET). An estimate of [123I]epidepride 'specific binding' to D2/D3 receptors was obtained in patients and age-matched healthy volunteers. A summary measure was generated representing striatal and temporal cortical relative %D2/D3 receptor occupancy by antipsychotic drugs. Occupancy data were compared with previously studied groups of patients receiving typical antipsychotic drugs (n=12) and clozapine (n=10). RESULTS: Mean striatal and temporal cortical %D2/D3 receptor occupancy in olanzapine-treated patients was 41.3% (SD 17.9) and 82.8% (SD 4.2), respectively. Unexpectedly low levels of striatal relative %D2/D3 receptor occupancy were seen in two patients with typical antipsychotic-drug-induced movement disorder prior to switching to olanzapine. In the temporal cortex, mean D2/D3 dopamine receptor occupancy levels above 80% were seen for all antipsychotic drugs studied. CONCLUSIONS: The atypical antipsychotic drugs olanzapine and sertindole, in common with clozapine, demonstrate higher occupancy of temporal cortical than striatal D2/D3 dopamine receptors in vivo at clinically useful doses. This could help mediate their atypical clinical profile of therapeutic efficacy with few extrapyramidal side effects. Limbic selective blockade of D2/D3 dopamine receptors could be a common action of atypical antipsychotic drugs.

In vivo 5-HT2A receptor blockade by quetiapine: an R91150 single photon emission tomography study.

BACKGROUND: Atypical antipsychotic drugs are thought to show a high degree of 5-HT2A receptor blockade, which may prevent the emergence of extrapyramidal symptoms. METHOD: 5-HT2A binding was estimated using 123I-5-I-R91150 and single photon emission tomography (SPET) in six schizophrenic subjects treated with quetiapine at a mean (+/-SD) daily dose of 350+/-123 mg for at least 5 weeks and a matched sample of six healthy volunteers. Clinical and side-effect ratings were performed at baseline and at the time of SPET scanning. The reference region approach was used to define a 5-HT2A binding index in the frontal and temporal cortex. RESULTS: Quetiapine treatment resulted in a significant decline in 5-HT2A receptor availability in the frontal cortex (mean 0.98+/-0.09) relative to healthy volunteers (mean 1.33+/-0.16). All patients showed improvements in clinical symptom or side-effect ratings. The mean frontal cortex:cerebellum ratio after quetiapine treatment was significantly negatively correlated with reduction in the Abnormal Involuntary Rating scale and Simpson-Angus scores (P<0.05 Bonferroni corrected), but not with the reduction in the scores from the scale for the assessment of positive symptoms, the scale for the assessment of negative symptoms, the Montgomery-Asberg depression rating scale or patient age. CONCLUSION: Quetiapine treatment results in significant in vivo blockade of cortical 5-HT2A, similar to other atypical antipsychotic drugs. This effect may contribute to its placebo level extrapyramidal side-effect profile.

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.

Schizophrenic auditory hallucinations are associated with increased regional cerebral blood flow during verbal memory activation in a study using single photon emission computed tomography.

Single photon emission tomography with split-dose technetium-99m-d, l-hexamethyl-propylene amine oxime was used to measure regional cerebral blood flow (rCBF) during a memory-activation paradigm in a group of 18 medicated DSM-III-R schizophrenic patients. The relationship between clinical features of schizophrenia and rCBF patterns was examined. Increased blood flow to the left basal ganglia was revealed during activation in patients reporting hallucinations in the previous month, a finding that was not influenced by medication dose or other confounding variables. This result adds to previous functional imaging studies that have related basal ganglia abnormalities to hallucinatory phenomena and suggests that left basal ganglia hyperactivity may be relevant to an internal monitoring deficit responsible for the appearance of those symptoms in schizophrenia.

Caudate regional cerebral blood flow in obsessive-compulsive disorder, panic disorder and healthy controls on single photon emission computerised tomography.

We compared regional cerebral blood flow (rCBF) in 15 patients with DSM IIIR obsessive-compulsive disorder (OCD), 15 patients with DSM IIIR panic disorder and 15 healthy controls matched for age, sex and hand preference, using uptake of technetium-99m-D,L-hexamethyl-propylene amine oxime (99mTc HMPAO), on single photon emission computerised tomography (SPECT). Caudate rCBF was significantly reduced in OCD patients compared to healthy subjects and panic disorder patients. When four patients were excluded from each group, right caudate rCBF remained significantly lower in OCD patients than in panic disorder patients or healthy subjects. The data suggest functional involvement of the right caudate nucleus is present in OCD.

Probing targets for antipsychotic drug action with PET and SPET receptor imaging.

The use of in vivo receptor imaging by positron emission tomography (PET) and single photon emission tomography (SPET) has permitted exploration of targets for antipsychotic drug action in living patients. Early PET and SPET studies focused on striatal D2 dopamine receptors. There is broad agreement that unwanted extrapyramidal (parkinsonian) side effects of antipsychotic drugs result from high striatal dopamine D2/D3 receptor blockade by these drugs. The dopamine hypothesis of antipsychotic drug action suggests that clinical response is directly related to the level of striatal D2/D3 receptor occupancy of antipsychotic drugs. This may be true for classical antipsychotic drugs, but recent evidence suggests that novel, atypical antipsychotic drugs produce efficacy in association with modest and transient striatal D2/D3 receptor occupancy levels. Furthermore, atypical antipsychotic drugs appear to show preferential occupancy of limbic cortical dopamine D2 receptors. Cortical dopamine D2/D2-like receptors may be a common site of action for all antipsychotic drugs. Data from receptor challenge paradigms has highlighted the need to explore the neurotransmitter systems involved in regulating or stabilising dopamine transmission, either via dopamine autoreceptors or non-dopaminergic pathways. These may be promising targets for drug development. In vivo PET and SPET imaging has produced unique data contributing to the design of better, less toxic drugs for schizophrenia.

Probing cortical sites of antipsychotic drug action with in vivo receptor imaging.

Imaging receptors using radioactive ligands has allowed direct determination of the sites of action of antipsychotic drugs. Initial studies relating antipsychotic drug efficacy to action at striatal dopamine D2-like receptors have recently been undermined. Developments in imaging extrastriatal dopamine D2-like receptors suggest rather that antagonism of these receptors in the temporal cortex is the common site of action for antipsychotic drugs, with occupancy at striatal receptors relating more closely to extrapyramidal side effects. Further work into dopamine receptor subtypes and other receptor groups such as serotonin and GABA neurotransmitters awaits the development of suitable probes, but there are some initial finding. Again a main site of antipsychotic drug action is at cortical levels with high degrees of cortical D1 and 5HT2a receptor occupancy attained particularly by atypical antipsychotic drugs.

Psychopharmacology of olanzapine. A review.

Olanzapine is a new atypical antipsychotic (Weaver, 1997). Both early development and clinical studies support its safe use. Clinical trials suggest that it is efficacious in treating positive symptoms in schizophrenia, and more efficacious for negative symptoms and depressive symptoms than traditional antipsychotics. In addition, the side-effect profile of olanzapine is favourable, with a low incidence of EPS and little increase in prolactin during acute-phase trials. At present, olanzapine appears broadly as good as the other novel atypical drugs. As a group, the atypical antipsychotics have been recommended for use as first-line therapy, in acute schizophrenic relapse, and for those who are responsive, but intolerant, to classical antipsychotic medication (Kerwin, 1994; Lieberman, 1996). The role of olanzapine in treating treatment-resistant patients is unproven, and data is awaited comparing olanzapine directly with clozapine. The current era of development of drugs for schizophrenia holds great promise, and it is the duty of all doctors to make patients aware of the benefits and risks of available treatments, and to enable them to choose.

Treating first episode psychosis--the service users' perspective: a focus group evaluation.

UK national guidance has prioritized developing specialist services for first episode psychosis. Such services are in the early stages of development and a definitive treatment model has yet to be established. The aim of this study was to explore service users' experiences of a first episode intervention designed along evidence-based 'best practice' guidelines and to establish specific elements seen as effective to help inform future service planning and provision. Twelve users of a specialist first episode service participated in focus groups. These were then analyzed using Interpretative Phenomenological Analysis, a specialized form of content analysis. Key elements identified by the service users included the 'human' approach as a key to the recovery process, being involved in treatment decisions, flexibility of appointments, high nurse to patient ratio, reduction in psychotic symptoms, increased confidence and independence and the provision of daily structure. To our knowledge, this is the first systematic qualitative evaluation of users' experience of a specialist first episode treatment intervention. Our findings indicate that adherence to best practice guidelines was appreciated. Regular focus groups provide a continuous audit cycle incorporating service improvements in line with government recommendations, centrally informed by the service users' and caregivers' perspective.