Search

Olfactory identification deficits and their relationship to negative symptoms in patients with schizophrenia were examined in patients with recent-onset psychosis, the majority of whom were neuroleptic naive.Seventy-four inpatients with a first episode of psychosis (27 with schizophrenia or schizophreniform disorder, nine with schizoaffective disorder, 17 with affective psychoses, and 21 with other psychoses), 49 of whom had not received antipsychotic medication, were compared to 38 age- and gender-matched normal subjects. Olfactory identification ability was assessed with the University of Pennsylvania Smell Identification Test. Forty patients and 13 comparison subjects were reassessed at 6 months to examine whether olfactory deficits were specific to schizophrenia or schizophreniform disorder and were stable over time.At baseline, the patients had significant impairment in olfactory identification ability compared to the normal subjects. This difference persisted after controlling for gender, premorbid or current IQ, smoking history, cannabis use, or the effects of medication. Diagnostic subgroups did not differ in olfactory identification ability. The deficits remained stable at 6-month follow-up and were associated with negative symptoms at both time points. No relationship was found between olfactory identification ability and length of either untreated psychosis or illness prodrome.Impairment in olfactory identification ability was apparent from the outset of psychotic illness and was not specific to schizophrenia or schizophreniform disorder. No change in the degree of this deficit was found after patients were stabilized and had responded to medication. The deficit could not be explained by peripheral factors that might contribute to olfactory identification ability, suggesting that it reflects central mechanisms.

ObjectiveThe delivery of biological markers for schizophrenia would greatly assist preventative strategies by identifying at-risk individuals who could then be monitored and treated in a manner with a view to minimising subsequent morbidity. This paper aims to present a selection of biological measures that may indicate risk of schizophrenia.MethodA selective and brief review is provided of intensively studied putative markers, including enlarged cerebral ventricles, dopamine D2receptor density, amphetamine-stimulated central nervous system dopamine release, plasma homovanillic acid and smooth pursuit eye tracking dysfunction.ResultsA number of biological measures have been reported to be correlated with schizophrenia.ConclusionsPresently, none of these measures has satisfactory performance characteristics in terms of predictive validity, noninvasiveness, ease of testing and low cost that would enable their widespread use. However, a few have potential for further investigation and development.

BACKGROUND: Acetylcholine is important to hippocampal function, including the processes of learning and memory. Patients with schizophrenia show impaired learning and memory and hippocampal dysfunction. Thus, acetylcholinergic systems may be primarily or secondarily disrupted in the hippocampal formation of schizophrenic patients. The present study tested the hypothesis that [(3)H]pirenzepine-labeled muscarinic cholinergic receptor levels are altered in the hippocampal formation of patients with schizophrenia. METHODS: We have used quantitative autoradiography to measure [(3)H]pirenzepine binding to M(1) and M(4) receptors in the hippocampal formation from 15 schizophrenic and 18 nonschizophrenic subjects. RESULTS: The mean density of [(3)H]pirenzepine binding was reduced in all regions studied, including the dentate gyrus, subdivisions of Ammon's Horn (CA1-CA4), subiculum, and the parahippocampal gyrus, of the schizophrenic cohort. Moreover, unlike controls, there was no significant variation between the mean levels of [(3)H]pirenzepine binding across the subregions of the hippocampal formation from schizophrenic subjects. CONCLUSIONS: These findings provide support for a possible involvement of the muscarinic cholinergic system in the pathology and/or treatment of schizophrenia.

[(3)H]ketanserin binding to 5HT(2A) receptors was measured in the left planum temporale (sensory speech cortex) from schizophrenic and non-schizophrenic (control) subjects using both particulate membranes and tissue sections. There was a significant decrease in the affinity of [(3)H]ketanserin binding to particulate membranes from schizophrenic subjects who were treated with phenothiazines up to death. Adding 2nM chlorpromazine to brain tissue from control subjects caused a similar decrease in the affinity of [(3)H]ketanserin binding to particulate membranes. This suggests that the decrease in affinity observed in the phenothiazine-treated subjects was due to residual drugs. In addition, there was a significant decrease in the density of [(3)H]ketanserin binding in both particulate membranes and tissue sections from schizophrenic subjects which did not appear to be due to residual antipsychotic drugs. Analysis of the laminar distribution of 5HT(2A) receptors showed that this decrease was greatest in cortical layer III. The decrease in the density of 5HT(2A) receptors was significant whether schizophrenic subjects were receiving phenothiazines or haloperidol at the time of death, and there was no correlation between the last recorded dose of antipsychotic drug and 5HT(2A) receptor density. These data suggest that a decrease in the density of 5HT(2A) receptors in the planum temporale may be associated with the pathology of schizophrenia.

Dopamine (DA) plays an important role in cognition, neuroendocrine functions and psychosis.1,2 Whilst stress adversely affects some of these functions, its neurobiological basis remains unclear.3 In the rat hypothalamus, a concurrent activation of D5and D2 receptors by dopamine produces a biphasic effect on the function of atrial natriuretic factor (ANF) neurons.4 Whereas low doses (10-8 and 10-7 M) of DA suppress the release and pro-ANF mRNA expression, high doses (10-6 and 10-5 M) of the amine produce an opposite effect through the interaction of D5 and D2 receptors. We report here that the augmenting effect of DA on the hypothalamic neurons is inhibited by a synthetic glucocorticoid, dexamethasone (DM), in both time-dependent and dose-related manner with an EC50 of 0.1 nM. Furthermore, the inhibition is blocked by 100 nM of RU38486 (P

OBJECTIVE: Data from a full assessment of auditory perception in patients with schizophrenia were used to investigate whether auditory hallucinations are associated with abnormality of central auditory processing. METHOD: Three groups of subjects participated in auditory assessments: 22 patients with psychosis and a recent history of auditory hallucinations, 16 patients with psychosis but no history of auditory hallucinations, and 22 normal subjects. Nine auditory assessments, including auditory brainstem response, monotic and dichotic speech perception tests, and nonspeech perceptual tests, were performed. Statistical analyses for group differences were performed using analysis of variance and Kruskal-Wallis tests. The results of individual patients with test scores in the severely abnormal range (more than three standard deviations from the mean for the normal subjects) were examined for patterns that suggested sites of dysfunction in the central auditory system. RESULTS: The results showed significant individual variability among the subjects in both patient groups. There were no group differences on tests that are sensitive to low brainstem function. Both patient groups performed poorly in tests that are sensitive to cortical or high brainstem function, and hallucinating patients differed from nonhallucinating patients in scores on tests of filtered speech perception and response bias patterns on dichotic speech tests. Six patients in the hallucinating group had scores in the severely abnormal range on more than one test. CONCLUSIONS: Hallucinations may be associated with auditory dysfunction in the right hemisphere or in the interhemispheric pathways. However, comparison of results for the patient groups suggests that the deficits seen in hallucinating patients may represent a greater degree of the same types of deficits seen in nonhallucinating patients.

This paper summarises the available information on MRI-determined hippocampal morphometry in first-episode patients as an illustration of the value and interpretation of findings in the neurobiology of early phase schizophrenia. We report a thin slice (1.5 mm) study of 32 first episode and 39 high risk patients which demonstrated significantly smaller hippocampi (right −9%, left −11%) in first episode patients that were of a similar magnitude to those found in chronic patients (right −10%, left −11%) but non-significant volume reductions in high risk individuals, including the 15 subjects who subsequently developed psychoses. Consideration is given to the implications of these findings, including the possible role of early and later neurodevelopmental influences. We present animal data showing that chronic placental insufficiency, as elicited by uterine artery ligation can give rise to substantial reduction (31%) in hippocampal volumes and reflect on other potentially relevant pathophysiological mechanisms, including those that may occur during the early phases of psychotic illnesses, including their prodromes. Greater attention needs to be paid to the study of early phase psychosis in order to obtain a clearer understanding of the nature and time course of neurobiological changes associated with it. Although there is a growing literature on first episode psychosis, there is a striking dearth of information on the neurobiology of the prodrome.

Studies using tissue obtained at autopsy suggest that changes in cholinergic neurons could be important in the pathology of schizophrenia.1-4 We have previously reported a decrease in [3H]pirenzepine binding5 and [3H]AF-DX 384 binding6 to caudate-putamen (CP) from subjects who had schizophrenia. Under the conditions chosen, [3H]pirenzepine would predominately bind to muscarinic1 (M1) and muscarinic4 (M4) receptors,7whereas [3H]AF-DX 384 would mainly bind to muscarinic2 (M2) and M4 receptors.8 Given the relative concentrations of M1, M2 and M4 receptors in the human CP and the magnitude of the decreases in radioligand binding in schizophrenia, our results most likely reflected a change in the density of M1 and M2 receptors in the CP from the schizophrenic subjects. In situ hybridisation has now been used to determine levels of m1 and m2 mRNA in CP from 14 schizophrenic and 16 control subjects previously used for radioligand binding. m2 mRNA in the CP from the schizophrenic and control subjects was below the sensitivity of in situhybridisation. There was no difference in the levels of m1 mRNA in CP from schizophrenic and control subjects (mean +/- SEM: 103 +/- 16 vs106 +/- 17 fmol [35S]oligonucleotide probe g-1estimated tissue equivalents, P = 0.91). In conclusion, data from our radioligand binding studies show decreases in [3H]pirenzepine binding that are likely to reflect a decrease in the density of M1 receptors in CP from schizophrenic subjects. Our data in this study show the absence of a concomitant change in mRNA coding for that receptor.

Background. Quetiapine (ICI 204,636, ‘Seroquel’) is a new atypical antipsychotic agent with a similar binding profile to the original atypical antipsychotic, clozapine. Its clinical efficacy has already been demonstrated at multiple fixed doses (150–750 mg/day) and has been suggested to be comparable with haloperidol (12 mg/day).Methods. This international, 6-week, multicentre, double-blind, randomized, parallel-group trial compared quetiapine with haloperidol (455 mg and 8 mg mean total daily doses, respectively) in 448 hospitalized patients with acute exacerbation of chronic or subchronic schizophrenia (DSM-III-R), in order to establish their equivalence in terms of efficacy, and the nature of their tolerability profiles, especially in terms of extrapyramidal symptoms (EPS) and serum prolactin levels.Results. Both quetiapine and haloperidol produced a clear reduction in the Positive and Negative Syndrome Scale (PANSS) scores and Clinical Global Impression (CGI) Severity of Illness and Global Improvement scores. At day 42, the PANSS total score was reduced by −18·7±1·63 in the quetiapine group, and −22·1±1·63 in the haloperidol group (P = 0·13, between-treatment).Quetiapine was better tolerated than haloperidol in terms of EPS as demonstrated by the significant differences in the Simpson Scale and Abnormal Involuntary Movement Scale scores (PConclusion. Quetiapine is an effective and well tolerated antipsychotic of comparable efficacy to haloperidol and lacks the latter compound's effect on prolactin and EPS.

Clinical studies of cholinergic pharmacotherapy, together with the putative role of the muscarinic receptor system in the neurophysiology of human behavior, support a possible muscarinic cholinergic involvement in schizophrenia. The present study has measured the density of [ 3 H]AF-DX 384 labelled receptors (muscarinic M 2 and M 4 ) in the caudate-putamen, obtained at autopsy, from 19 subjects who had schizophrenia, and 20 subjects who did not have schizophrenia. [ 3 H]AF-DX 384 binding was reduced in caudate-putamen from schizophrenic subjects (104 ± 10.3 ν s 145 ± 901 fmol mg −1 TE; mean ± s.e.; p = 0.007). Preliminary analysis of patient drug data as well as rat studies suggest that the reduced [ 3 H]AF-DX 384 binding in caudate-putamen of schizophrenic subjects is not wholly due to antipsychotic drug treatment, or anticholinergic medication for the treatment of extrapyramidal effects. These data suggest that the muscarinic cholinergic system may be involved in the pathology of schizophrenia.

Having shown a decrease in serotonin 2A receptors in the dorsolateral prefrontal cortex (DLPFC) from schizophrenic subjects, we have now determined if this change was reflective of widespread changes in neurochemical markers in DLPFC in schizophrenia. In Brodmann's area (BA) 9 from 19 schizophrenic and 19 control subjects, we confirmed a decrease in the density of [ 3 H]ketanserin binding to serotonin 2A receptors in tissue from the schizophrenic subjects [39 ± 3.3 vs. 60 ± 3.6 fmol/mg estimated tissue equivalents (ETE); p < 0.005]. In addition, the density of [ 3 H]muscimol binding to GABA A receptors was increased in the schizophrenic subjects (526 ± 19 vs. 444 ± 28 fmol/mg ETE; p < 0.02). [ 3 H]YM-09151-2, N-[1-(2-thienyl)cyclohexyl]-3,4-[ 3 H]piperidine, [ 3 H]SCH 23390, [ 3 H]mazindol, and NG-nitro-L-[ 3 H]arginine binding to BA 9 did not differ between groups, and there was no specific binding of [ 3 H]raclopride or 7-hydroxy-2-(di-n-[3H]propylamino)tetralin to BA 9 from either cohort of subjects. This suggests the density of dopamine D 1 -like and NMDA receptors, the dopamine transporter, and nitric oxide synthase activity are not altered in BA 9 from schizophrenic subjects. The selective nature of the changes in serotonin 2A and GABA A receptors in DLPFC could indicate that these changes are involved in the pathology of schizophrenia.

Changes in serotonin receptors and the serotonin transporter have been reported in the dorsolateral prefrontal cortex from subjects with schizophrenia, an area of the brain thought to be important in the pathology of the illness. To further our understanding on how such changes could play a role in the pathology of the illness, in situ radioligand binding with autoradiography was used to measure the density of the serotonin 1A receptor, the serotonin 4 receptor and the serotonin transporter in the dorsolateral prefrontal cortex, obtained at autopsy, from 10 schizophrenic and 10 control subjects. The binding of [ 3 H]8-OH-DPAT to serotonin 1A receptor, [ 3 H]GR113808 to the 5HT 4 receptor and [ 3 H]citalopram to serotonin transporter was not altered in subjects with schizophrenia. Significantly, only in tissue from the control subjects was there a relationship between age and the density of the serotonin 4 receptor in Brodmanns areas 8 ( r = 0.71, P = 0.02) and 10 ( r = −0.67, P = 0.03). Importantly, this confounding factor did not influence the comparison of the density of serotonin 4 receptor in the tissue from the schizophrenic and control subjects. This study has failed to show a difference in the density of serotonin 1A receptor, the serotonin 4 receptor or the serotonin transporter in the dorsolateral prefrontal cortex (Brodmanns areas 8, 9 and 10) from subjects with schizophrenia. These data suggest that not all serotonergic markers are altered in the dorsolateral prefrontal cortex from schizophrenic subjects.

Kallmann syndrome and schizophrenia share several clinical features, including dysfunctional olfactory ability, hypogonadotrophic hypogonadism, an excess of affected males, and psychiatric presentation. Because of this congruence, it has been proposed that up to 70% of male schizophrenics might have mutations affecting the function or expression of the gene mutated in Kallmann syndrome, KAL-X. We identified and studied 9 unrelated males with schizophrenia (as defined by DSM-IIIR criteria) who also have severe anosmia (first percentile of normal range) and low sex drive (seventh percentile of the normal range), and we sequenced the exons and the intron-exon junctions of the KAL-X gene for each. We found no mutations, and conclude that schizophrenia is rarely, if ever, due to a mutation in the coding sequence or splice junctions of KAL-X.

Whereas progesterone and dopamine share a common central pathway to modulate sexual behavior in female rats, the way in which estrogen is involved remains unclear. In a long-term rat hypothalamic cell culture system, atrial natriuretic factor-producing neurons were identified as candidate sites for integration of sex steroid action. Estrogen induces the expression of progesterone receptors in atrial natriuretic factor neurons and also augments neuronal functions by increasing expression of constitutively active D5 receptors that generate cAMP in a ligand-independent manner. Such a cross-talk mechanism allows estrogen to exert its effects via the adenylyl cyclase-cAMP system by augmenting dopamine receptor activity, an action that may play an important integrative role in facilitating female sexual behavior.

This study attempted to localize regions of brain electrical activity associated with the onset of auditory hallucinations. Changes in Steady State Visually Evoked Potential (SSVEP) topography associated with the onset of spontaneous auditory hallucinations was studied in eight schizophrenic patients. The SSVEP elicited by a spatially uniform sinusoidally varying visual flicker was recorded using a 64-channel electrode helmet. A large and significant decrease in SSVEP latency in the right temporo/parietal region occurred in the second prior to the report of auditory hallucinations. A control task with matching motor movements produced no significant decrease in SSVEP latency in the same right temporo/parietal location. This finding suggests that activity of fine temporal resolution in the neural networks in the right temporo/parietal area may be implicated in the genesis of auditory hallucination, in conformity with certain neuropsychological theories.

Allelic association case-control analysis of a deletion/insertion polymorphism in the serotonin transporter-linked polymorphic region (5-HTTLPR) has suggested associations with unipolar disorder, bipolar disorder, depression, and Alzheimer’s disease. Moreover, the heterozygous long form of the 5-HTTLPR has been associated with increased levels of mRNA for the serotonin transporter (5-HTT) and increased serotonin uptake in lymphoblastic cell lines. This study attempts to determine whether there is an association between 5-HTTLPR genotype and schizophrenia or the binding of [3H]paroxetine to the human hippocampal 5-HTT. DNA from the cerebellum from 58 schizophrenic and 62 control subjects was used to genotype the 5-HTTLPR. In addition, the relationship between 5-HTTLPR genotype and the affinity and density of [3H]paroxetine binding to the hippocampal 5-HTT was assessed. There were no associations between 5-HTTLPR allotype or genotype and/or the parameters of [3H]paroxetine binding to the hippocampal 5-HTT. Our data suggest that 5-HTTLPR genotype neither confers an increased susceptibility for schizophrenia nor dictates the expression of the 5-HTT in the human hippocampus.

The binding of [ 3 H]nemonapride to human postmortem caudate and putamen tissue was autoradiographically investigated using several antipsychotic drugs. Saturation experiments revealed a single population of binding sites (dissociation constant ( K D ) 0.38 ± 0.01 nM, and total binding capacity ( B MAX ) 55 fmol/TE). Prototypic dopamine (DA) receptors antagonists displaced [ 3 H]nemonapride in a monophasic manner. The order of displacement potency was expected for DA D 2 -like receptors: spiperone > (+)butaclamol ≥ chlorpromazine > (−)sulpiride > ketanserin. Displacement with serotonergic antagonists suggests that in human caudate and putamen tissue [ 3 H]nemonapride may have a very low affinity serotonergic component. However, [ 3 H]nemonapride displays a high affinity and selectivity for DA D 2 -like receptors and should make it a preferred compound for tritium-based autoradiography.

Objective: To review the contemporary landscape regarding pharmacological treatments for schizophrenia. Method: Selective literature review. Results: Newer antipsychotic agents include aripiprazole, asenapine, paliperidone, sertindole and ziprasidone. Each has some particular benefits and some shortcomings. Overall treatment efficacy (for positive symptoms at least) has not advanced substantially but some newer agents might have a better profile than older typical agents for negative and cognitive symptoms. Metabolic side effects and hyperprolactinaemia remain a problem with some of the newer agents and appropriate monitoring is required. Conclusions: Whilst newer antipsychotics have been welcome additions to our pharmacological armamentarium, mostly in terms of tolerability, we have still not seen a ‘quantum leap’ agent brought to market. Mechanisms of action apart from post-synaptic dopamine blockade appear worthy of further investigation in this regard.

Dopamine (DA) D2 receptors which act by modulating second messenger pathways that include protein kinase C (PKC) and adenylate cyclase (AC) have been repeatedly shown to be increased in striatum from subjects with schizophrenia. Therefore it seemed possible that chronic up-regulation of DA-D2 receptors in the schizophrenic brain could result in a change in either of these two proteins. Hence we measured PKC and AC in striatum from 20 schizophrenic subjects and 20 non-schizophrenic subjects by quantitative autoradiography and could show no difference in the density of either PKC (436 +/- 35 vs. 485 +/- 29 fmol/mg tissue equivalents (TE), mean +/- SEM) or AC (77 +/- 9 vs. 80 +/- 7 fmol/mg TE) in the tissue from schizophrenic compared to the non-schizophrenic subjects. Thus, these data do not support the hypothesis that PKC or AC are changed in the schizophrenic brain.

The effect of treating rats with daily injections of haloperidol (1mg/kg/day) or clozapine (20 mg/kg/day) for four weeks on second messengers and dopamine receptors was studied. The binding of [ 3 H]forskolin to adenylate cyclase (AC), [ 3 H]phorbol 12,13-dibutyrate (PDBu) to protein kinase C (PKC), [ 3 H]SCH23390 binding to the dopamine D 1 (DA-D 1 ) receptor and [ 3 H]spiperone binding to the dopamine D 2 (DA-D 2 ) receptor were measured using quantitative autoradiography. The density of AC was greatest in the caudate-putamen, nucleus accumbens and olfactory tubercle, a distribution resembling that of DA-D 1 receptor. The distribution of PKC was relatively homogeneous in the forebrain. Neither haloperidol nor clozapine administration significantly altered the levels of AC or PKC in the caudate-putamen. By contrast treatment with haloperidol, but not clozapine, significantly increased the density of DA-D 2 receptors in the caudate-putamen without affecting the density of DA-D 1 receptors. By contrast, both haloperidol and clozapine increased the density of DA-D 1 receptors in the olfactory tubercle.

This study was a preliminary open clinical trial aimed at exploring the hypothesis that estrogen may provide protection against schizophrenia in women. Eleven women with acute psychotic symptoms, as scored on the BPRS, SAPS and SANS, had 0.02 mg estradiol added to neuroleptic treatment for eight weeks. Their response was compared to seven women with similar symptom severity receiving neuroleptic treatment alone. Both groups had baseline hormonal assays of estrogen, progesterone, LH and FSH and underwent regular psychopathology ratings during the eight weeks. The group receiving the estradiol adjunct showed more rapid improvement in psychotic symptoms compared with the group receiving neuroleptics only. This difference was not sustained for the entirety of the trial. Both groups reached similar levels of recovery by the eighth week. These results suggest that estradiol may have antipsychotic properties and/or act as a catalyst for neuroleptic responsiveness in women with schizophrenia.

Obiective : The purpose of this study was to determine 1) the reliability of diagnoses of schizophrenia at coronal autopsy and 2) the degree to which the use of different diagnostic instruments for schizophrenia would affect postmortem brain research. Method : Eighty-three subjects, recorded at coronal autopsy as having had schizophrenia, were referred for neuro-chemistry studies. The diagnoses reported to the state coroner's office were reevaluated by a review of psychiatric case histories by clinicians using semistructured assessment and diagnostic criteria. Results : The application of DSM-III-R, Research Diagnostic Criteria (RDC), ICD-10, Schneiderian, and Feighner criteria to the diagnosis of the 83 subjects revealed that 63.9%, 48.2%, 48.2%, 43.4%, and 42.2%, respectively, met the criteria for schizophrenia. Highest concordance was between the RDC and ICD-10 systems, while lowest concordance was between the RDC and Schneider systems. Conclusions : These data suggest that unless carefully reviewed, diagnosis may be a major confounding factor in postmortem studies ofbrain tissue from subjects with schizophrenia.

Many patients with psychotic disorders experience persistent auditory hallucinations despite rigorous pharmacological treatment. The experience of auditory hallucinations can heighten anxiety and depression. The high risk of suicide among patients experiencing auditory hallucinations is well recognized. Research in this area has been restricted to small samples or has collected information only on the use of such strategies without investigating their efficacy. The Mental Health Research Institute Unusual Perceptions Schedule incorporates a module focusing on coping strategies. This schedule was administered to 100 subjects, with the aim of investigating the relationship between strategy use and effectiveness, as well as the characteristics of subjects and their disorders. Eighty-one percent of the subjects were worried or upset by their hallucinations. The majority (66%) of the subjects reported they had ways of managing the voices, and 69% of them described at least some success using one or more strategies. There was a striking lack of correspondence between the number of subjects using a method and its related efficacy. No relationship was found between length of illness and number of strategies used. Multidimensional scaling of use and efficacy data revealed three groups of strategies. These groups do not correspond to previous classifications made on the basis of features of the strategies themselves. The pattern of results also suggests that training methods might be used to increase the options for patients troubled by auditory hallucinations.

Besides acting as an important cofactor in the biosynthesis of catecholamine, ascorbic acid (AA) also modulates the activity of peptidylglycine-alpha-amidating monooxygenase for the post-translational modification of neuropeptides such as alpha-MSH and TRH. We report here a novel action of AA in modulating the secretion of immunoreactive beta-endorphin (ir-beta EP) and mRNA expression of proopiomelanocortin (POMC) following the activation of cAMP-dependent protein kinase A pathway in rat hypothalamic neurons. Primary cultures of hypothalamic neurons from neonatal rats as previously described were employed in the present studies. Six days after plating, cultures were replenished with serum-free media and incubated with vehicle or various doses of AA in the presence or absence of forskolin, 3-isobutyl-1-methylxanthine (IBMX), N6,2'-O-dibutyryladenosine 3'5'-(cyclic)monophosphate [(Bu)2cAMP]. Whereas the basal ir-beta EP release was 22.0 +/- 0.4 pg/well (mean +/- S.E.; n = 3), 10 microM of forskolin treatment increased ir-beta EP release approximately 4.2-fold. Co-incubation with AA enhanced forskolin induced ir-beta EP release and that this enhancing effect of AA was both time related and dose-dependent, with an ED50 of approximately 10 microM and an Emax of 100 microM. At the concentration of 10 microM, AA augmented ir-beta EP release approximately 6.1-fold that of cultures treated with forskolin alone. A similar potentiating effect of AA was also seen in cultures co-treated with IBMX or with (Bu)2cAMP. These enhancing effects of AA were similarly found in the abundance of total cAMP and of POMC mRNA of cultures which received identical treatments. However, it is important to point out that AA alone did not modulate ir-beta EP release or the abundance of POMC mRNA or total cAMP levels of the hypothalamic cultures when protein kinase A pathway was not activated. We thus conclude that AA augments cAMP-dependent protein kinase A pathway-induced production and release of beta EP from rat hypothalamic neurons in culture. Furthermore, this biological effect of AA is, at least in part, mediated through enhancing the responsiveness of the adenylyl cyclase-cAMP system.

A comprehensive understanding of the phenomenology of auditory hallucinations (AHs) is essential for developing accurate models of their causes. Yet, only 1 detailed study of the phenomenology of AHs with a sample size of N ≥ 100 has been published. The potential for overreliance on these findings, coupled with a lack of phenomenological research into many aspects of AHs relevant to contemporary neurocognitive models and the proposed (but largely untested) existence of AH subtypes, necessitates further research in this area. We undertook the most comprehensive phenomenological study of AHs to date in a psychiatric population (N = 199; 81% people diagnosed with schizophrenia), using a structured interview schedule. Previous phenomenological findings were only partially replicated. New findings included that 39% of participants reported that their voices seemed in some way to be replays of memories of previous conversations they had experienced; 45% reported that the general theme or content of what the voices said was always the same; and 55% said new voices had the same content/theme as previous voices. Cluster analysis, by variable, suggested the existence of 4 AH subtypes. We propose that there are likely to be different neurocognitive processes underpinning these experiences, necessitating revised AH models.

Bipolar disorder is characterized by progressive changes in cognition with declines in executive functioning, memory and sustained attention. Current pharmacotherapies for bipolar disorder target mood symptoms but have not addressed these cognitive changes resulting in euthymic individuals who still experience cognitive deficits. N-acetyl cysteine (NAC) has been shown to have effects on antioxidant status, glutamate transmission, inflammation and neurogenesis. Adjunctive treatment with NAC improves the symptoms experienced by those with bipolar disorder, particularly depression, and it was hypothesized that cognition may also be improved following NAC treatment.As part of a larger randomized, double-blind, placebo-controlled trial, participants in the current report were tested at baseline and 6 months to assess changes in cognitive function following either 2000 mg of NAC daily or placebo.This study failed to find changes in cognitive function following treatment with NAC compared to placebo.While an important pilot study, this study had a small sample size and included a limited battery of cognitive tests. Further investigations on the effects of NAC on cognitive performance in bipolar disorder are required.

The binding of [ 3 H]paroxetine and [ 3 H]ketanserin to particulate membranes from frontal cortex of subjects who had or did not have schizophrenia was measured as was [ 3 H]paroxetine binding to particulate membranes from the hippocampus and caudate nucleus. There was no change in either the affinity or density of [ 3 H]ketanserin binding to membranes from the frontal cortex of subjects who had schizophrenia. Similarly, there was no difference in the density of [ 3 H]paroxetine binding to membranes from subjects who had or did not have schizophrenia. The affinity of [ 3 H]paroxetine binding in the frontal cortex and putamen did not differ in subjects who had schizophrenia. By contrast, there was a significant decrease in the affinity of [ 3 H]paroxetine binding to the hippocampal membrane from subjects who had schizophrenia (0.40 ± 0.06 nM vs 0.26 ± 0.02 nM ; p < 0.05). Furthermore, this difference was more apparent in the subjects who had schizophrenia and committed suicide (0.49 ± 0.09 nM) than it was in those who had schizophrenia but did not commit suicide (0.32 ± 0.09 nM). As [ 3 H]ketanserin binds to the serotonin 2 receptor our data suggest that this receptor is not changed in the Brodmann's area 9 of the frontal cortex. By contrast, [ 3 H]paroxetine binds to the serotonin transporter and therefore our data suggest that the serotonin transporter is altered in the hippocampus of subjects with schizophrenia.

Antipsychotics, both the long established typical drugs and the recently introduced atypical drugs clozapine and risperidone, are highly effective in acute and maintenance treatment of schizophrenia. However, typical antipsychotics are associated with tardive dyskinesia after long term use, and many other clinical situations arise for which discontinuation of therapy may be appropriate. For patients who have recovered from a first episode of psychosis, it is recommended that antipsychotics are continued for 1 to 2 years before withdrawal is considered. Patients who have experienced recurrent psychotic episodes need long term maintenance treatment and there is no simple guide as to when discontinuation might be attempted. The risk of potentially dangerous psychotic relapse is high in most circumstances. Long term prognosis may also be worsened by the occurrence of repeated psychotic relapses. Additionally, there can be withdrawal reactions, which are mostly attributable to cholinergic rebound. The problems of discontinuation are minimised by very gradual dosage reduction and, occasionally, the temporary addition of anticholinergic medications. A key principle for maintenance treatment is the use of the lowest effective dose of antipsychotic, established by trial and error. If discontinuation of typical antipsychotic medication is essential, an option is to switch to risperidone or clozapine. Because of the problems associated with both continuation and withdrawal of antipsychotics, the decision to discontinue should be made with the informed consent of the patient and their carers.

Remoxipride, a substituted benzamide, is a selective D-2 antagonist with an atypical neuroleptic profile. Previous studies have demonstrated its antipsychotic efficacy against haloperidol and, more recently, thioridazine. Of the 144 patients enrolled in the Australian remoxipride-thioridazine comparative trial, 28 presented for their first episode of schizophrenia and/or had no previous neuroleptic treatment. These patients form the subject of this paper.

The Mental Health Research Institute Unusual Perceptions Schedule (MUPS) is a comprehensive instrument developed to record subjects' experiences of auditory hallucinations as completely as possible. The Schedule comprises a semi-structured interview and documents the physical characteristics of auditory hallucinations such as their onset and course, number, volume, tone, location, as well as other phenomena associated with them such as delusions. In addition, other aspects of hallucinations, such as coping strategies, contributing factors and subjects' personal views and reactions are also explored. In a sample of 100 subjects drawn primarily from the in-patient wards at Royal Park Hospital the MUPS was found to be an acceptable instrument to subjects in the field. Interrater reliability assessed in a subsample of 30 subjects was found to be high at the level of the individual items. Whether used in whole or part, the MUPS provides a reliable and acceptable method of assessing patients' experience of auditory hallucinations.

Although N-terminal truncated forms of atrial natriuretic factor (ANF) are produced and released from rat hypothalamic neurons, the intrahypothalamic regulation of these processes remains unclear. Employing a well-characterized hypothalamic cell culture system, we report here that dopamine, mediating through D 2 receptors, inhibits the synthesis and release of ANF. In long-term cultures of hypothalamic neurons, daily treatment for 4 days with quinpirole, a D 2 agonist, significantly suppressed the basal irANF release in a time-related and a dose-dependent manner. The ED 50 and E max of the drugs were 9.1 × 10 -8 M and 10 -5 M , respectively. This effect of quinpirole was mimicked by 10 -7 M of dopamine, a physiological ligand for D 2 receptor. Furthermore, the suppressing effects of both quinpirole and dopamine were abolished by sulpiride, a D 2 antagonist. Whereas 10 -6 M of forskolin treatment consistently enhanced the release of irANF through activating the adenylyl cyclase-cAMP system, this stimulatory effect was suppressed by quinpirole in a dose-related manner. In addition, the application of pertussis toxin, a bacterial toxin which inactivated G i protein activity, reversed the suppressing effect of quinpirole or dopamine on irANF release. These immunoassay findings were accompanied by corresponding changes in the abundance of pro-ANF mRNA in the cultures as determined by colorimetric Northern blot analysis. By combining the techniques of in situ hybridization and immunocytochemistry, the mRNA of D 2 receptor was colocalized with irANF at a single cell level by double fluorescent staining. We thus conclude that the release and gene expression of ANF in rat hypothalamic neurons are directly suppressed by dopamine acting through its D 2 receptors on ANF neurons. This inhibitory effect is likely to be mediated, at least in part, through G i protein-induced suppression of the adenylyl cyclase-cAMP system.

Altered [3H] dopamine uptake by platelet-rich plasma (PRP) has been reported in some subjects with schizophrenia (Rotman et al 1980; Dean et al 1990). As platelet dopamine uptake was measured using PRP, it was not possible to determine if the changes in schizophrenia were intrinsic to the platelet or due to plasma factors. Furthermore, the constraints of plasma as a medium for platelet suspension has hindered the study of the physiological requirements of platelet dopamine uptake. A method is now reported that allows platelets to be suspended in a controlled medium while preserving the dopamine uptake mechanism of the platelet. Dopamine uptake by platelets in a controlled medium was dependent on temperature, energy, sodium, and chloride. Furthermore, plasma from subjects with schizophrenia and schizophreniform disorder did not significantly alter [3H] dopamine uptake by platelets compared to the effect of plasma from control subjects. Hence, these data provide no evidence for a circulating inhibitor of platelet [3H] dopamine uptake in plasma from subjects with schizophrenia.

Twenty-four, first-admission, psychotic subjects and 24 control subjects were administered a linguistic instrument to elicit impairments in syntax, semantics, cohesion, and use of metaphors. In the same session, the subjects were also rated on the Scale for Thought, Language, and Communication Disorders (TLC). Results indicated a significant impairment of all four linguistic categories in psychotic subjects. The impairment in semantics, however, was differentiated the most between the patient and control groups. The psychotic patients scored significantly higher on the TLC. Scores of impairment on the linguistic tasks did not correlate with scores on the TLC.

Beta-endorphin(beta EP)1-31, a potent opioid peptide of proopiomelanocortin (POMC) derivatives, is produced and released from neurons at arcuate nuclei of the rat hypothalamus. Although dexamethasone (DM) suppresses the production and secretion of POMC related peptides from rat pituitary corticotrophs, the effect of glucocorticoids on the function of hypothalamic beta EP neurons remains unclear. Employing long term monolayer cultures of neonatal rat hypothalamic cells, we report here that 4 day treatment with 10 microM of forskolin increased ir-beta EP levels in cell content and culture media by approximately 1.7 (P0.05) and 4.1 times (P0.01) above vehicle treated control cultures (mean +/- S.E.M., 47.3 +/- 2.6 pg/well and 40.4 +/- 3.0 pg/well; n = 3) respectively. Although 4 day treatment with DM alone had little effect on the release and the cell content of ir-beta EP, it significantly enhanced forskolin-induced elevation of ir-beta EP levels in cell content and in culture media. The effect of DM was dose-related and time-dependent, with an EC50 of about 1 nM; at this concentration DM enhanced ir-beta EP secretion about 2.1 times (P0.01) above that induced by 10 microM of forskolin alone. Furthermore, the potentiating effect of DM was specifically suppressed by 100 nM of RU38486 (P0.01), a glucocorticoid receptor antagonist, but not by an equivalent dose of RU28318, a mineralocorticoid receptor antagonist. In addition, Northern blot analysis showed that forskolin (10 microM) increased the abundance of POMC mRNA 1.4 fold above that of vehicle treated control cultures. Whereas by itself, DM (10 nM) had little effect on the level of POMC mRNA, it enhanced forskolin-stimulated increase of the abundance of POMC mRNA approximately 2.6 times. Moreover, DM also augmented 1.6 times (P0.05) forskolin-induced but not 3-isobutyl-1-methylxanthine (IBMX)-induced increase of cAMP production (5.5 +/- 0.4 pmol/well; mean +/- S.E.M., n = 3) in the cultures. Taken together, our findings suggest that in contrast to the inhibitory effect on pituitary corticotrophs, glucocorticoids enhance the production and secretion of beta EP from rat hypothalamic neurons by facilitating the stimulatory effect mediated, in part, through the adenylyl cyclase-cAMP system.

The present study investigated the factor structure of the items contained in Andreasen's scales for the assessment of positive and negative symptoms (SAPS and SANS) by use of a series of principal components analyses (PCAs) with oblique rotations of the axes. It was found that the structure could be summarized by three major components labeled negative symptoms, thought disorder, and delusions/hallucinations. Dimensionality could meaningfully be increased to five components. Negative symptoms was found to separate into two components that we labeled negative signs and social dysfunctions. The delusions/hallucinations factor could be separated into two components, delusions and hallucinations, with "loss of boundary" delusions being related to both factors. Delusions of persecution were independent of other symptoms. The thought disorder factor did not decompose meaningfully within the investigated dimensionality. A two-factor solution did not explain the correlation between symptoms adequately. The results do not support the simple dichotomy between positive and negative symptoms in psychosis, but suggest that a wider dimensional concept may be more useful in future studies.

A study of cannabinoid application in vitro showed that THC appears to accumulate primarily in neurons and that transformation to its metabolite, THC-COOH, depends on the presence of glia. The authors suggested that the adverse effects of cannabinoids on the brain may occur through a combination of pathways involving cannabinoid receptor activation, accumulation of cannabinoids and their metabolites and upregulation of neuroinflammatory cytokines. Findings of persistent alteration of brain function or cognitive impairment in human cannabis users support the notion that long-term cannabis use may result in morphological alterations of brain structures that subserve attention, learning, memory, executive functions and emotional processes. Since brain structural changes are evident in patients with schizophrenia, cannabis may exert greater adverse effects on brain morphology when the brain is already compromised. This chapter proposes that long-term heavy cannabis use leads to structural brain changes and associated deleterious functional sequelae that resemble aspects of schizophrenia.

OBJECTIVE: In this report, we aimed to evaluate the effect of add-on N-acetylcysteine (NAC) on depressive symptoms and functional outcomes in bipolar disorder. To that end, we conducted a secondary analysis of all patients meeting full criteria for a depressive episode in a placebo controlled trial of adjunctive NAC for bipolar disorder. METHOD: Twenty-four week randomised clinical trial comparing adjunctive NAC and placebo in individuals with bipolar disorder experiencing major depressive episodes. Symptomatic and functional outcome data were collected over the study period. RESULTS: Seventeen participants were available for this report. Very large effect sizes in favor of NAC were found for depressive symptoms and functional outcomes at endpoint. Eight of the ten participants on NAC had a treatment response at endpoint; the same was true for only one of the seven participants allocated to placebo. DISCUSSION: These results indicate that adjunctive NAC may be useful for major depressive episodes in bipolar disorder. Further studies designed to confirm this hypothesis are necessary.

Oxidative stress and reduced brain levels of glutathione have been implicated in schizophrenia and bipolar disorder. N-acetyl cysteine (NAC) is a precursor of glutathione and has additional effects on glutamate neurotransmission, neurogenesis and inflammation. While NAC treatment has shown benefits in both schizophrenia and bipolar disorder, the mechanisms of action are largely unknown. Similarly, the interaction between oxidative stress and altered dopaminergic activities in psychiatric illness is not yet characterized. This study investigated the capacity of NAC in restoring brain glutathione depletion in rats that received 2-cyclohexene-1-one (CHX, 75 mg/kg), d -amphetamine (2.5 mg/kg) or both. CHX, but not amphetamine, induced significant depletion of glutathione levels in the striatum and frontal cortex. Glutathione depletion was reversed by NAC (1000 mg/kg) in saline-treated and amphetamine-treated (frontal cortex only) rats. While NAC was shown to be beneficial in this model, the lack of additional glutathione depletion by amphetamine in combination with CHX does not support a summative interaction between oxidative stress and altered dopamine transmission.

In rats, opioidergic beta-endorphin (beta EP1-31) is produced and released from neurons of arcuate nuclei in the hypothalamus. Although the neuropeptide has been implicated in sexual maturation and stress-induced reproductive dysfunction, the intra-hypothalamic regulation of beta EP neurons remains unclear. Employing long-term monolayer cultures of neonatal rat hypothalamic cells, we report here that 4 days of treatment with 10 microM forskolin increased approximately 3-fold (P < 0.01) the proportion of immunoreactive (ir)-beta EP positive neurons bearing neurites. In addition, treatment of forskolin also enhanced ir-beta EP release (634 +/- 59 pg/well; mean +/- SE, n = 4, P < 0.01) by 14-fold and ir-beta EP content (119 +/- 13 pg/well; P < 0.01) by 2-fold above that of vehicle-treated cultures; in both instances, the EC50 and the Emax of forskolin were approximately 10 microM and 100 microM, respectively. The forskolin-stimulated release of ir-beta EP was mimicked by cholera toxin and (Bu)2cAMP treatment in a dose-related manner, but not by pertussis toxin. Although by itself 3-isobutyl-1-methyl-xanthine (100 microM) only doubled ir-beta EP secretion, it markedly potentiated the stimulatory effect of forskolin. This forskolin-induced stimulation was reversible and in cultures re-exposed to the same drug within the first 24 h period, there was a marked increase in the stimulated release of ir-beta EP (P < 0.05); re-challenge of forskolin at later stages, however, induced a smaller but significant secretion of ir-beta EP (P < 0.01) compared to that of vehicle-treated control cultures. Sephadex G-50 gel chromatographic profile of the media prepared from forskolin-treated cultures revealed a major ir-beta EP peak of 3 K M(r). High-performance liquid chromatography analysis showed that ir-beta EP of the 3 K M(r) species was eluted with a retention time similar to that of synthetic rat beta EP1-31. We thus conclude that the adenylyl cyclase-cAMP system plays an important role in the modulation of beta EP1-31 production and release from hypothalamic beta EP neurons in culture. Furthermore, the functional responsiveness and the morphological development of these neurons are affected, at least in part, by the intrinsic activity of the adenylyl cyclase-cAMP system.

The validity of the simple dichotomy between positive and negative symptoms was examined by reanalysing the results of published studies using global ratings from Andreasen's SAPS and SANS. Global ratings from our own sample of 114 diagnostically heterogenous psychotic patients were also analysed. In none of the studies was a simple positive-negative dichotomy an adequate representation of symptom structure. The most commonly occurring structure consisted of three independent groups: Hallucinations/Delusions, Positive Thought Disorder and Negative Symptoms. These findings applied to both manic and schizophrenic groups of patients. An important implication of these results for future studies is that combining positive symptoms into a single scale is inappropriate because possibly differential relationships between Hallucinations/Delusions and Thought Disorder and a variety of external measures may be obscured by such a means of data reduction.

Command hallucinations represent a special problem for the clinical management of psychosis. While compliance with both non-harmful and harmful commands can be problematic, sometimes in the extreme, active efforts to resist commands may also contribute to their malignancy. Previous research suggests Cognitive Behaviour Therapy (CBT) to be a useful treatment for reducing compliance with harmful command hallucinations. The purpose of this trial was to evaluate whether CBT augmented with acceptance-based strategies from Acceptance and Commitment Therapy could more broadly reduce the negative impact of command hallucinations. Forty-three participants with problematic command hallucinations were randomized to receive 15 sessions of the intervention "TORCH" (Treatment of Resistant Command Hallucinations) or the control, Befriending, then followed up for 6 months. A sub-sample of 17 participants was randomized to a waitlist control before being allocated to TORCH or Befriending. Participants engaged equally well with both treatments. Despite TORCH participants subjectively reporting greater improvement in command hallucinations compared to Befriending participants, the study found no significant group differences in primary and secondary outcome measures based on blinded assessment data. Within-group analyses and comparisons between the combined treatments and waitlist suggested, however, that both treatments were beneficial with a differential pattern of outcomes observed across the two conditions.

Dopamine is taken up by platelets by an energy and temperature dependent process that does not involve a known dopamine receptor. Whilst dopamine uptake by platelets has been shown to be altered in several disease states, little is known about factors controlling dopamine uptake by platelets which could cause such changes. As phorbol esters have been shown to affect dopamine functions in other tissues we examined the effect of phorbol esters on dopamine uptake by human platelets. Phorbol 12,13-dibutyrate increased [(3)H]-dopamine uptake by platelets in a dose dependent manner. Similarly, phorbol 12,13-didecanoate increased [(3)H-dopamine uptake by platelets but 4α phorbol 12,13-didecanoate, which does not affect protein kinase, did not. Staurosporin, a protein kinase inhibitor, reversed the effect of phorbol 12,13-dibutyrate. These data suggest protein kinases can modulate dopamine uptake by platelets.

Background The evidence base for the pharmacological treatment of bipolar II disorder is limited. In bipolar disorder, there is evidence for glutathione depletion and increased oxidative stress, as well as dysregulation of glutamate; N-acetyl cysteine (NAC) has effects on both of these systems. Add-on NAC has been shown to have a significant benefit on depressive symptoms in a randomized placebo-controlled trial. In this report, we explore the effects of this compound in a subset of patients with bipolar II disorder from that trial. Methods Individuals were randomized to NAC or placebo in addition to treatment as usual, in a double-blind fashion. Mood and functional outcomes were assessed up to 24 weeks of treatment. Results Fourteen individuals were available for this report, seven in each group. Six people achieved full remission of both depressive and manic symptoms in the NAC group; this was true for only two people in the placebo group (χ2 = 4.67, p = 0.031). Limitations Subgroup analyses in a small subsample of patients. Not all participants had elevated depression scores at baseline. Conclusion Notwithstanding all the limitations that subgroup analysis of trials carry, this data could serve as a hypothesis-generating stimulus for further clinical trials of pharmacologic treatment for bipolar II depression.

Recently, the validity of the simple dichotomy between positive and negative symptoms in psychosis has been questioned. A newly admitted group of 114 DSM-III patients with psychotic disorder were assessed using Andreason's positive and negative symptoms scales. Multidimensional scaling, augmented by cluster analysis, was applied to the full item set of these scales and showed clearly that there are three major, independent groups of symptoms: Hallucinations/Delusions, Positive Thought Disorder and Negative Symptoms. Within the Hallucinations/Delusions and Negative Symptoms groups there was some additional structure which does not conform to the SAPS and SANS sub-scales. In particular there was considerable heterogeneity within the Hallucinations/Delusions group, and delusions of persecution may represent a fourth independent dimension of psychopathology which is under-represented in these scales.