Association study of functional polymorphisms of dopaminergic pathway in epilepsy-related factors of temporal lobe epilepsy in Brazilian population.

BACKGROUND AND PURPOSE: There are few data about the role of neurotransmission modulated by dopamine in epilepsy, especially temporal lobe epilepsy (TLE). This is the first study that aimed to analyze the dopaminergic polymorphisms in an etiologically homogeneous group of patients with TLE with hippocampal sclerosis. Selected polymorphisms were: (i) the most expressed D2-like receptors in the limbic system (DRD2/ANKK1 TAQ-1A, D4_VNTR and D4_rs1800955); (ii) the dopamine transporter (DAT) 3'-untranslated region and intron 8; and (iii) two degrading enzymes regulating the synaptic activity, i.e. the main metabolizer of dopamine, catechol-O-methyltransferase, and monoamine oxidase A. METHODS: We assessed 119 patients with unequivocal TLE with hippocampal sclerosis and 112 healthy volunteers. Individuals were genotyped for the polymorphisms of the gene encoding dopaminergic pathway transporter DAT haplotype, dopaminergic receptors, catechol-O-methyltransferase and monoamine oxidase A. We also evaluated epilepsy-related factors (e.g. seizure frequency, age of onset, duration and status epilepticus). RESULTS: There was no difference between the groups for the studied polymorphisms. The polymorphism DRD4_VNTR was associated with family history of epilepsy (P = 0.003), DRD2_rs1800497 was related to status epilepticus (P = 0.022), and intron 8 VNTR DAT was related to higher seizure frequency (P = 0.019) and family history of epilepsy (P = 0.011). CONCLUSIONS: Our findings demonstrated that polymorphisms of the dopaminergic pathway are associated with significant clinical features of this form of epilepsy, such as seizure frequency, family history of epilepsy and status epilepticus.

State-dependent microstructural white matter changes in drug-naïve patients with first-episode psychosis.

BACKGROUND: Diffusion tensor imaging (DTI) studies have consistently shown white matter (WM) microstructural abnormalities in schizophrenia. Whether or not such alterations could vary depending on clinical status (i.e. acute psychosis v. remission) remains to be investigated. METHODS: Twenty-five treatment-naïve first-episode psychosis (FEP) patients and 51 healthy-controls (HC) underwent MRI scanning at baseline. Twenty-one patients were re-scanned as soon as they achieved sustained remission of symptoms; 36 HC were also scanned twice. Rate-of-change maps of longitudinal DTI changes were calculated for in order to examine WM alterations associated with changes in clinical status. We conducted voxelwise analyses of fractional anisotropy (FA) and trace (TR) maps. RESULTS: At baseline, FEP presented reductions of FA in comparison with HC [p < 0.05, false-discovery rate (FDR)-corrected] affecting fronto-limbic WM and associative, projective and commissural fasciculi. After symptom remission, patients showed FA increase over time (p < 0.001, uncorrected) in some of the above WM tracts, namely the right anterior thalamic radiation, right uncinate fasciculus/inferior fronto-occipital fasciculus, and left inferior fronto-occipital fasciculus/inferior longitudinal fasciculus. We also found significant correlations between reductions in PANSS scores and FA increases over time (p < 0.05, FDR-corrected). CONCLUSIONS: WM changes affecting brain tracts critical to the integration of perceptual information, cognition and emotions are detectable soon after the onset of FEP and may partially reverse in direct relation to the remission of acute psychotic symptoms. Our findings reinforce the view that WM abnormalities in brain tracts are a key neurobiological feature of acute psychotic disorders, and recovery from such WM pathology can lead to amelioration of symptoms.

Neurobiological support to the diagnosis of ADHD in stimulant-naïve adults: pattern recognition analyses of MRI data.

OBJECTIVE: In adulthood, the diagnosis of attention-deficit/hyperactivity disorder (ADHD) has been subject of recent controversy. We searched for a neuroanatomical signature associated with ADHD spectrum symptoms in adults by applying, for the first time, machine learning-based pattern classification methods to structural MRI and diffusion tensor imaging (DTI) data obtained from stimulant-naïve adults with childhood-onset ADHD and healthy controls (HC). METHOD: Sixty-seven ADHD patients and 66 HC underwent high-resolution T1-weighted and DTI acquisitions. A support vector machine (SVM) classifier with a non-linear kernel was applied on multimodal image features extracted on regions of interest placed across the whole brain. RESULTS: The discrimination between a mixed-gender ADHD subgroup and individually matched HC (n = 58 each) yielded area-under-the-curve (AUC) and diagnostic accuracy (DA) values of up to 0.71% and 66% (P = 0.003) respectively. AUC and DA values increased to 0.74% and 74% (P = 0.0001) when analyses were restricted to males (52 ADHD vs. 44 HC). CONCLUSION: Although not at the level of clinically definitive DA, the neuroanatomical signature identified herein may provide additional, objective information that could influence treatment decisions in adults with ADHD spectrum symptoms.

A Selective Association between Central and Peripheral Lithium Levels in Remitters in Bipolar Depression: A 3T-(7) Li Magnetic Resonance Spectroscopy Study.

OBJECTIVE: The objective of this study was to evaluate brain lithium levels using (7) Li magnetic resonance spectroscopy after 6 weeks of lithium therapy in bipolar depression to test the hypothesis that brain and plasma lithium are correlated. It was also tested whether responders and remitters have different pharmacokinetics, blood and brain lithium levels (ratio) compared with those presenting suboptimal antidepressant improvement. METHOD: Twenty-three patients with bipolar disorder (I and II) during depressive episodes were included and followed up for 6 weeks at the University of Sao Paulo using flexible dose of lithium (450-900 mg/day). Sixteen patients were drug-naïve. At endpoint, patients underwent a (7) Li-MRS scan and brain lithium concentrations were calculated. RESULTS: A significant association between central and peripheral lithium levels was found only in remitters (r = 0.7, P = 0.004) but not in non-remitters (r = -0.12, P = 0.76). Also, brain lithium (but not plasma) was inversely correlated with age (r = -0.46, P = 0.025). Plasma lithium did not correlate with any clinical outcome, lithium dosage or adverse effects. CONCLUSION: These findings suggest that non-remitters may not transport lithium properly to the brain, which may underlie treatment resistance to lithium in BD. Future studies with (7) Li-MRS integrated with the evaluation of blood-brain barrier transport mechanisms and longitudinal clinical outcomes in BD and aging are warranted.

What determines continuing grey matter changes in first-episode schizophrenia and affective psychosis?

BACKGROUND: Magnetic resonance imaging (MRI) studies have shown that brain abnormalities in psychosis might be progressive during the first years of illness. We sought to determine whether first-episode psychosis (FEP) subjects show progressive regional grey matter (GM) changes compared with controls, and whether those changes are associated with diagnosis, illness course or antipsychotic (AP) use. METHOD: Thirty-two subjects with first-episode schizophrenia-spectrum disorders (FESZ), 24 patients with first-episode affective psychoses (FEAP) and 34 controls recruited using a population-based design underwent structural MRI scanning at baseline and at a 5-year follow-up. Regional GM volumes were assessed with voxel-based morphometry (VBM). Patients were treated at community settings, and about half of them remained mainly untreated. RESULTS: No significant progressive changes in GM regional volumes were observed in either the FESZ or FEAP group overall. However, FESZ subjects with a non-remitting course showed GM decrements in the left superior temporal gyrus (STG) and insula relative to remitted FESZ subjects. Non-remitted FEAP subjects exhibited a GM decrease in the dorsolateral prefrontal cortex (DLPFC) bilaterally in comparison to remitted FEAP subjects. Among FESZ subjects, AP use was associated with regional GM decrements in the right insula and increments in the cerebellum. CONCLUSIONS: Our results suggest that the progression of brain abnormalities in FEP subjects is restricted to those with a poor outcome and differs between diagnosis subgroups. AP intake is associated with a different pattern of GM reductions over time.

Longitudinal follow-up of cavum septum pellucidum and adhesio interthalamica alterations in first-episode psychosis: a population-based MRI study.

BACKGROUND: Neurodevelopmental alterations have been described inconsistently in psychosis probably because of lack of standardization among studies. The aim of this study was to conduct the first longitudinal and population-based magnetic resonance imaging (MRI) evaluation of the presence and size of the cavum septum pellucidum (CSP) and adhesio interthalamica (AI) in a large sample of patients with first-episode psychosis (FEP). METHOD: FEP patients (n=122) were subdivided into schizophrenia (n=62), mood disorders (n=46) and other psychosis (n=14) groups and compared to 94 healthy next-door neighbour controls. After 13 months, 80 FEP patients and 52 controls underwent a second MRI examination. RESULTS: We found significant reductions in the AI length in schizophrenia FEP in comparison with the mood disorders and control subgroups (longer length) at the baseline assessment, and no differences in any measure of the CSP. By contrast, there was a diagnosis×time interaction for the CSP length, with a more prominent increase for this measure in the psychosis group. There was an involution of the AI length over time for all groups but no diagnosis×time interaction. CONCLUSIONS: Our findings suggest that the CSP per se may not be linked to the neurobiology of emerging psychotic disorders, although it might be related to the progression of the disease. However, the fact that the AI length was shown to be shorter at the onset of the disorder supports the neurodevelopmental model of schizophrenia and indicates that an alteration in this grey matter junction may be a risk factor for developing psychosis.

Lack of progression of brain abnormalities in first-episode psychosis: a longitudinal magnetic resonance imaging study.

BACKGROUND: Some neuroimaging studies have supported the hypothesis of progressive brain changes after a first episode of psychosis. We aimed to determine whether (i) first-episode psychosis patients would exhibit more pronounced brain volumetric changes than controls over time and (ii) illness course/treatment would relate to those changes. METHOD: Longitudinal regional grey matter volume and ventricle:brain ratio differences between 39 patients with first-episode psychosis (including schizophrenia and schizophreniform disorder) and 52 non-psychotic controls enrolled in a population-based case-control study. RESULTS: While there was no longitudinal difference in ventricle:brain ratios between first-episode psychosis subjects and controls, patients exhibited grey matter volume changes, indicating a reversible course in the superior temporal cortex and hippocampus compared with controls. A remitting course was related to reversal of baseline temporal grey matter deficits. CONCLUSIONS: Our findings do not support the hypothesis of brain changes indicating a progressive course in the initial phase of psychosis. Rather, some brain volume abnormalities may be reversible, possibly associated with a better illness course.

Neuroimaging in cannabis use: a systematic review of the literature.

BACKGROUND: We conducted a systematic review to assess the evidence for specific effects of cannabis on brain structure and function. The review focuses on the cognitive changes associated with acute and chronic use of the drug. METHOD: We reviewed literature reporting neuroimaging studies of chronic or acute cannabis use published up until January 2009. The search was conducted using Medline, EMBASE, LILACS and PsycLIT indexing services using the following key words: cannabis, marijuana, delta-9-tetrahydrocannabinol, THC, cannabidiol, CBD, neuroimaging, brain imaging, computerized tomography, CT, magnetic resonance, MRI, single photon emission tomography, SPECT, functional magnetic resonance, fMRI, positron emission tomography, PET, diffusion tensor MRI, DTI-MRI, MRS and spectroscopy. RESULTS: Sixty-six studies were identified, of which 41 met the inclusion criteria. Thirty-three were functional (SPECT/PET/fMRI) and eight structural (volumetric/DTI) imaging studies. The high degree of heterogeneity across studies precluded a meta-analysis. The functional studies suggest that resting global and prefrontal blood flow are lower in cannabis users than in controls. The results from the activation studies using a cognitive task are inconsistent because of the heterogeneity of the methods used. Studies of acute administration of THC or marijuana report increased resting activity and activation of the frontal and anterior cingulate cortex during cognitive tasks. Only three of the structural imaging studies found differences between users and controls. CONCLUSIONS: Functional neuroimaging studies suggest a modulation of global and prefrontal metabolism both during the resting state and after the administration of THC/marijuana cigarettes. Minimal evidence of major effects of cannabis on brain structure has been reported.

The influence of lithium on hippocampal volume in elderly bipolar patients: a study using voxel-based morphometry.

Recent studies have demonstrated that lithium (Li) exerts neuronal protective and regenerative effects both in vitro and in vivo. However, the effects of long-term Li treatment in the brain areas associated with memory impairment of elderly bipolar patients are still unknown. The aim of this study was to compare the hippocampal volumes of elderly bipolar patients using Li, elderly bipolar patients not using Li and healthy controls. Sociodemographic, clinical and magnetic resonance imaging data from 30 elderly euthymic bipolar patients who had been using Li for an average of >61 months; 27 elderly euthymic bipolar patients not taking Li for an average of 45 months; and 22 elderly healthy controls were analyzed. Volumetric differences in the hippocampus between groups were investigated with voxel-based morphometry (VBM) based on the Statistical Parametric Mapping technique. No statistical differences in sociodemographic and clinical characteristics and course of bipolar disorder between the two bipolar groups were observed. Using small volume correction in the VBM analysis (analysis of variance (ANOVA)), one voxel cluster of statistical significance was detected in the left hippocampus (P<0.05 corrected for multiple comparisons, extent threshold >10 voxels). Post hoc unpaired t-tests revealed increased left hippocampal volume in the Li-treated group compared with the non-Li-treated group, and decreased left hippocampal volume in the non-Li group relative to controls. Additional exploratory two-group comparisons indicated trends toward reduced right-hippocampal volumes in the non-Li-treated group relative to both the Li-treated group and controls. The findings suggested that the use of Li may influence the volume of the hippocampus, possibly due to its neuroprotective effects.

Late-life depression, heart failure and frontal white matter hyperintensity: a structural magnetic resonance imaging study.

The relevance of the relationship between cardiac disease and depressive symptoms is well established. White matter hyperintensity, a bright signal area in the brain on T2-weighted magnetic resonance imaging scans, has been separately associated with cardiovascular risk factors, cardiac disease and late-life depression. However, no study has directly investigated the association between heart failure, major depressive symptoms and the presence of hyperintensities. Using a visual assessment scale, we have investigated the frequency and severity of white matter hyperintensities identified by magnetic resonance imaging in eight patients with late-life depression and heart failure, ten patients with heart failure without depression, and fourteen healthy elderly volunteers. Since the frontal lobe has been the proposed site for the preferential location of white matter hyperintensities in patients with late-life depression, we focused our investigation specifically on this brain region. Although there were no significant group differences in white matter hyperintensities in the frontal region, a significant direct correlation emerged between the severity of frontal periventricular white matter hyperintensity and scores on the Hamilton scale for depression in the group with heart failure and depression (P = 0.016, controlled for the confounding influence of age). There were no significant findings in any other areas of the brain. This pattern of results adds support to a relationship between cardiovascular risk factors and depressive symptoms, and provides preliminary evidence that the presence of white matter hyperintensities specifically in frontal regions may contribute to the severity of depressive symptoms in cardiac disease.

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.

The psychiatric symptoms of rheumatic fever.

OBJECTIVE: This study examined the frequency and age at onset of psychiatric disorders among children with rheumatic fever, Sydenham's chorea, or both and a comparison group. METHOD: Twenty children with rheumatic fever, 22 with Sydenham's chorea, and 20 comparison children were assessed by means of a semistructured interview and rating scales for tic disorders and obsessive-compulsive disorder. RESULTS: Obsessive-compulsive symptoms were more frequent in both the Sydenham's chorea and rheumatic fever groups than in the comparison group. The Sydenham's chorea group had a higher frequency of major depressive disorder, tic disorders, and attention deficit hyperactivity disorder (ADHD) than both the comparison and rheumatic fever groups. ADHD symptoms were associated with a higher risk of developing Sydenham's chorea. CONCLUSIONS: Both the rheumatic fever and Sydenham's chorea groups were associated with a higher risk of developing neuropsychiatric disorders than the comparison group. ADHD appears to be a risk factor for Sydenham's chorea in children with rheumatic fever.

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.

Regional cerebral blood flow abnormalities in early-onset obsessive-compulsive disorder: an exploratory SPECT study.

OBJECTIVE: Recent epidemiological and clinical data suggest that obsessive-compulsive disorder (OCD) may be subtyped according the age of onset of obsessive-compulsive symptoms. The regional cerebral blood flow (rCBF) single photon emission computed tomography (SPECT) technique was used to investigate whether the pathophysiology of OCD differs between early- and late-onset OCD subjects. METHOD: Resting rCBF was measured in 13 early-onset (<10 years) and 13 late-onset (>12 years) adult OCD subjects and in 22 healthy controls. Voxel-based rCBF comparisons were performed with statistical parametric mapping. RESULTS: Early-onset OCD cases showed decreased rCBF in the right thalamus, left anterior cingulate cortex, and bilateral inferior prefrontal cortex relative to late-onset subjects (p < .0005, uncorrected for multiple comparisons). Relative to controls, early-onset cases had decreased left anterior cingulate and right orbitofrontal rCBF, and increased rCBF in the right cerebellum, whereas late-onset subjects showed reduced right orbitofrontal rCBF and increased rCBF in the left precuneus. In early-onset subjects only, severity of obsessive-compulsive symptoms correlated positively with left orbitofrontal rCBF. CONCLUSIONS: rCBF differences in frontal-subcortical circuits between early-onset and late-onset OCD subjects were found, both in location and direction of changes. These results provide preliminary evidence that brain mechanisms in OCD may differ depending on the age at which symptoms are first expressed.

Schizophrenia, psychosis, and the basal ganglia.

Schizophrenia is one of the most common and perhaps the most disabling of mental disorders, for which effective forms of treatment have not yet been established definitively. The findings reviewed in this article strongly suggest that basal ganglia abnormalities are involved in the pathophysiology of psychotic syndromes in general, and schizophrenia in particular.

Perspectives on the role of serotonergic mechanisms in the pharmacology of schizophrenia.

In recent years, a number of research findings has renewed interest in the possible role of serotonin (5-HT) in the pharmacology of schizophrenia. Atypical antipsychotics that potently block 5-HT receptors have been shown to be at least as effective as classical antipsychotics as well as producing fewer extrapyramidal side-effects. In addition, molecular biological studies have suggested that allelic variations of 5-HT receptor genes may affect both susceptibility to schizophrenia and clinical response to atypical antipsychotics. Building on these findings, this article proposes that 5-HT receptors are critical sites of antipsychotic action, and examines the implications of this to the treatment and pathophysiology of schizophrenia. Possible pharmacological mechanisms underlying the clinical efficacy of 5-HT blocking antipsychotics are discussed, and the potential of functional neuroimaging techniques to further elucidate these mechanisms is emphasized.

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.