Processing speed and working memory span: their differential role in superficial and deep memory processes in schizophrenia.

Previous work has suggested that decrement in both processing speed and working memory span plays a role in the memory impairment observed in patients with schizophrenia. We undertook a study to examine simultaneously the effect of these two factors. A sample of 49 patients with schizophrenia and 43 healthy controls underwent a battery of verbal and visual memory tasks. Superficial and deep encoding memory measures were tallied. We conducted regression analyses on the various memory measures, using processing speed and working memory span as independent variables. In the patient group, processing speed was a significant predictor of superficial and deep memory measures in verbal and visual memory. Working memory span was an additional significant predictor of the deep memory measures only. Regression analyses involving all participants revealed that the effect of diagnosis on all the deep encoding memory measures was reduced to non-significance when processing speed was entered in the regression. Decreased processing speed is involved in verbal and visual memory deficit in patients, whether the task require superficial or deep encoding. Working memory is involved only insofar as the task requires a certain amount of effort.

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

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

Serial and semantic encoding of lists of words in schizophrenia patients with visual hallucinations.

Previous research has suggested that visual hallucinations in schizophrenia are associated with abnormal salience of visual mental images. Since visual imagery is used as a mnemonic strategy to learn lists of words, increased visual imagery might impede the other commonly used strategies of serial and semantic encoding. We had previously published data on the serial and semantic strategies implemented by patients when learning lists of concrete words with different levels of semantic organisation (Brébion et al., 2004). In this paper we present a re-analysis of these data, aiming at investigating the associations between learning strategies and visual hallucinations. Results show that the patients with visual hallucinations presented less serial clustering in the non-organisable list than the other patients. In the semantically organisable list with typical instances, they presented both less serial and less semantic clustering than the other patients. Thus, patients with visual hallucinations demonstrate reduced use of serial and semantic encoding in the lists made up of fairly familiar concrete words, which enable the formation of mental images. Although these results are preliminary, we propose that this different processing of the lists stems from the abnormal salience of the mental images such patients experience from the word stimuli.

Production of atypical category exemplars in patients with schizophrenia.

Previous studies have revealed semantic memory impairments in patients with schizophrenia, and suggested that certain of these impairments were related to thought disorganization. One explanation offered for this is a broadening of the boundaries of semantic categories in schizophrenia. We selected 16 semantic categories, and required a sample of 41 schizophrenia patients and 43 healthy control subjects to produce one exemplar from each category. The typicality of the subjects' responses was rated. The exemplars produced by the patients were on average less typical than those produced by the healthy controls. No significant association between typicality of the response and thought disorganization was revealed in the patient sample. Affective flattening, alogia, and anhedonia were significantly and inversely associated with the typicality score, that is, higher ratings of these symptoms were associated with more typical responses. Our results suggest that a broadening of semantic category boundaries is observed in patients with schizophrenia, but is unrelated to thought disorganization. This semantic abnormality is not a feature of the patients with high ratings of certain negative symptoms.

Depression, avolition, and attention disorders in patients with schizophrenia: associations with verbal memory efficiency.

The authors undertook a study of the clinical correlates of verbal memory deficits in schizophrenia. The first purpose was to replicate the finding of a significant association between depression and impairment in the deep encoding memory processes. The second purpose was to test the hypothesis that certain clinical symptoms--avolition, disorders of attention--also play a role in verbal memory impairment, distinct from a global negative symptomatology score. Forty-one patients with schizophrenia underwent a memory task including forward digit span and learning lists of words with different levels of semantic organization. Regression analyses revealed that the depression score was associated with the total number of recalled words, whereas the global negative symptom score was not. Depression score was not associated with the forward digit span, a measure of superficial serial encoding processes. An analysis of individual symptoms from the Scale for the Assessment of Negative Symptoms (SANS) indicated that avolition was associated with several memory scores, suggesting a pervasive effect of this symptom. Attention disorders were associated with impaired efficiency in serial learning, but not with word recall efficiency. It is suggested that more consideration should be given to depression and motivation in the investigation of cognitive impairment in schizophrenia, as well as in cognitive remediation strategies.

Working memory span and motor and cognitive speed in schizophrenia.

OBJECTIVE: The aim of this study was to investigate the verbal working memory deficit and decrease of motor and cognitive speed in patients with schizophrenia, and to clarify their associations with negative and depressive symptomatology. METHODS: Forty patients with schizophrenia and 41 healthy control individuals were administered the backward digit span to assess the working memory capacity, along with 3 tests of processing speed. RESULTS: Patients demonstrated reduced backward digit span, as well as decreased motor and cognitive speed. Regression analyses indicated that the backward digit span was associated with cognitive speed. It was not associated with either negative or depressive symptoms. Decreased processing speed was unrelated to negative symptoms, but the depression score was significantly associated with the cognitive speed measure. CONCLUSIONS: Working memory and processing speed seem to share a cognitive component. Depression, but not negative symptoms, affects processing speed, especially by decreasing cognitive speed.

Cortical dopamine D2/D3 receptors are a common site of action for antipsychotic drugs--an original patient data meta-analysis of the SPECT and PET in vivo receptor imaging literature.

Subject numbers in neuroreceptor imaging studies of antipsychotic treatment in schizophrenia are generally insufficient to directly test the relationship of regional D(2)/D(3) and 5HT(2A) receptor binding to clinical efficacy. We selected positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies of antipsychotic dose vs occupancy at both temporal cortex and striatal D(2)/D(3) receptors. We selected corresponding SPECT and PET studies of 5HT(2A) receptor occupancy. We also selected randomized double-blind clinical trials of antipsychotics, where patients were treated with randomly assigned fixed doses. For each antipsychotic drug, we compared the optimum effective antipsychotic dose with the dose inducing maximal occupancy of D(2)/D(3) receptors in striatum and in temporal cortex as well as at 5HT(2A) receptors. Both first- and second-generation antipsychotic (FGA, SGA) drugs produced high temporal cortex D(2)/D(3) occupancy. Only FGA produced high striatal D(2)/D(3) receptor occupancy. The clinically effective dose showed correlation with doses inducing maximal dopamine D(2)/D(3) receptor occupancy both in striatum and in temporal cortex, the strongest correlation being with temporal cortex binding. Extrapyramidal side effects (EPSE) were primarily related to striatal D(2)/D(3) receptor occupancy. There was no correlation between 5HT(2A) occupancy and clinically effective dose. We conclude that cortical dopamine D(2)/D(3) receptor occupancy is involved in antipsychotic efficacy, with striatal D(2)/D(3) occupancy having a likely therapeutic role while also inducing EPSE. We found no evidence for 5HT(2A) blockade involvement in antipsychotic action, although we cannot exclude this possibility.

Role of processing speed and premorbid IQ on visual recognition in patients with schizophrenia.

Previous research had shown that processing speed and premorbid IQ are predictors of verbal-memory efficiency in patients with schizophrenia. We investigated whether the same factors are involved in visual memory. A total of 49 patients with schizophrenia and 43 healthy controls were administered a picture recognition task. Half of the pictures were black and white, and half were in color, in order to vary the depth of encoding. Processing speed was measured by three standard tasks, and premorbid IQ was measured by the National Adult Reading Test (NART). Patients were significantly impaired in picture recognition. Regression analyses revealed that NART score was a significant predictor of the recognition of both types of picture in patients. Processing speed was a significant predictor of the recognition of the colored pictures. The effect of diagnosis on the recognition of colored pictures was reduced to nonsignificance when processing speed was entered in the regression. These data suggest that premorbid IQ is involved in visual-recognition efficiency. However, the deficit observed in patients is accounted for by decreased processing speed.

Visual hallucinations in schizophrenia: confusion between imagination and perception.

OBJECTIVE: An association between hallucinations and reality-monitoring deficit has been repeatedly observed in patients with schizophrenia. Most data concern auditory/verbal hallucinations. The aim of this study was to investigate the association between visual hallucinations and a specific type of reality-monitoring deficit, namely confusion between imagined and perceived pictures. METHOD: Forty-one patients with schizophrenia and 43 healthy control participants completed a reality-monitoring task. Thirty-two items were presented either as written words or as pictures. After the presentation phase, participants had to recognize the target words and pictures among distractors, and then remember their mode of presentation. RESULTS: All groups of participants recognized the pictures better than the words, except the patients with visual hallucinations, who presented the opposite pattern. The participants with visual hallucinations made more misattributions to pictures than did the others, and higher ratings of visual hallucinations were correlated with increased tendency to remember words as pictures. No association with auditory hallucinations was revealed. CONCLUSIONS: Our data suggest that visual hallucinations are associated with confusion between visual mental images and perception.

Relationship between ketamine-induced psychotic symptoms and NMDA receptor occupancy: a [(123)I]CNS-1261 SPET study.

RATIONALE: Ketamine induces effects resembling both positive and negative psychotic symptoms of schizophrenia. These are thought to arise through its action as an uncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. OBJECTIVES: We used [(123)I]CNS-1261 to study ketamine binding to NMDA receptors in healthy human controls in vivo and its relationship to positive and negative psychotic symptom induction. MATERIALS AND METHODS: Ten healthy controls underwent two single-photon emission tomography scans with [(123)I]CNS-1261. On each occasion, they received a bolus infusion of either ketamine or saline. The Brief Psychiatric Rating Scale (BPRS) was administered at the end of each scan. Predefined regions of interest were used to estimate change in volume of distribution of [(123)I]CNS-1261 following ketamine administration. Two normalised-to-cortex binding indices were also used in order to study effects of ketamine on NMDA receptor availability by region, after correction for global and nonspecific effects. RESULTS: Ketamine-induced reduction in [(123)I]CNS-1261 volume of distribution in all regions showed the strongest correlation with BPRS negative subscale (p < 0.01). With the normalised-to-cortex measures, NMDA receptor binding in middle inferior frontal cortex showed a significant correlation with BPRS negative subscale (BI1 r = 0.88, BI2 r = 95.9, p < 0.001). CONCLUSIONS: [(123)I]CNS-1261 binding was modulated by ketamine, a drug known to compete for the same site on the NMDA receptor in vitro. Ketamine may induce negative symptoms through direct inhibition of the NMDA receptor, and positive symptoms may arise through a different neurochemical pathway.

Visual memory errors in schizophrenic patients with auditory and visual hallucinations.

Hallucinations have been found associated with false detection or false recognition of acoustic/verbal material in several studies. We investigated whether they were also linked with false recognition of pictures. Furthermore, an association between hallucinations and deficits in remembering temporal context was observed in previous research on schizophrenia. We investigated whether the association extends to deficits in remembering spatial context. Forty-one patients with schizophrenia underwent a visual memory task. Sixteen mixed black-and-white and colored pictures were presented at different locations. Participants had to recognize the pictures among distractors, then to recall the spatial context of the presentation of the target pictures. Results showed that auditory hallucinations were associated with poor recognition of the colored pictures. When recognition efficiency and negative symptoms were statistically controlled, auditory hallucinations were also associated with increased response bias toward false recognition of nontarget pictures, and with errors in remembering the spatial context. No associations with visual hallucinations emerged. Anhedonia was associated with response bias, in the direction opposite to that of hallucinations. In conclusion, the association between hallucinations and response bias extends across modalities to picture recognition. The association between hallucinations and temporal context impairment extends to spatial context.

Sexual function and gonadal hormones in patients taking antipsychotic treatment for schizophrenia or schizoaffective disorder.

OBJECTIVE: To determine rates of sexual dysfunction and hypogonadism and establish the relationship between gonadal hormone levels and sexual function in patients taking antipsychotic treatment for schizophrenia or schizoaffective disorder. METHOD: We studied 103 patients with schizophrenia or schizoaffective disorder (mean age = 46.2 (SD = 12.9) years; 51.5% male) from October 2003 through March 2005. Sexual function was assessed using the Sexual Functioning Questionnaire (SFQ) and compared with (1) normal controls (N = 62; mean age = 36.1 (SD = 9.6) years; 55% male) recruited from primary care attendees and (2) sexually dysfunctional controls recruited from a local sexual dysfunction clinic (N = 57; mean age = 39.1 (SD = 10.7) years; 79% male). Prolactin, sex hormone-binding globulin, testosterone, estradiol, progesterone, follicle-stimulating hormone, and luteinizing hormone levels; psychopathology; and side effects were measured. RESULTS: Mean (SD) total SFQ scores were significantly greater in patients (women = 9.9 [5.3]; men = 7.8 [4.9]) compared with normal controls (women = 4.1 [2.9]; men = 4.09 [2.95]), and similar to the scores of sexual dysfunction clinic attendees (women = 7.2 [2.9]; men = 9.9 [4.5]). The odds ratios of patients having sexual dysfunction compared with normal controls were 15.2 for women and 3.7 for men. Hypogonadism was common (in premenopausal women, 79% showed hypoestrogenism and 92% showed low progesterone levels, and 28% of men showed hypotestosteronism). There was no association between total SFQ scores and prolactin or gonadal hormone levels. CONCLUSION: Patients receiving treatment for schizophrenia or schizoaffective disorder show high rates of sexual dysfunction and hypogonadism. Sexual functioning was not related to prolactin or gonadal hormone levels.

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

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

Temporal context discrimination in patients with schizophrenia: associations with auditory hallucinations and negative symptoms.

BACKGROUND: A deficit in remembering the temporal context of events (a type of source memory) has been observed in schizophrenia, and suggested to be associated with positive symptoms. METHODS: In order to investigate memory for temporal context, we administered a list discrimination task to a sample of schizophrenia patients and a sample of healthy controls. Participants were required to learn two lists of mixed high- and low-frequency words separated by 10 min, then to remember whether each word had been presented in the first or in the second list. RESULTS: The number of misattributions to the wrong list was significantly higher in patients than in healthy controls. However, the group difference was eliminated when recall efficiency was covaried. The number of list misattributions was higher in patients with auditory hallucinations than in the other patients, independently of verbal recall efficiency. By contrast, affective flattening and anhedonia were associated with fewer list misattributions of the high-frequency words. CONCLUSIONS: It is suggested that auditory hallucinations are associated with deficit in processing or remembering the temporal context. Conversely, certain negative symptoms are associated with reduced temporal context errors. The possible neural mechanisms involved in temporal context deficit as well as in these specific clinical symptoms are discussed.

Role of processing speed and depressed mood on encoding, storage, and retrieval memory functions in patients diagnosed with schizophrenia.

The role of various types of slowing of processing speed, as well as the role of depressed mood, on each stage of verbal memory functioning in patients diagnosed with schizophrenia was investigated. Mixed lists of high- and low-frequency words were presented, and immediate and delayed free recall and recognition were required. Two levels of encoding were studied by contrasting the relatively automatic encoding of the high-frequency words and the more effortful encoding of the low-frequency words. Storage was studied by contrasting immediate and delayed recall. Retrieval was studied by contrasting free recall and recognition. Three tests of motor and cognitive processing speed were administered as well. Regression analyses involving the three processing speed measures revealed that cognitive speed was the only predictor of the recall and recognition of the low-frequency words. Furthermore, slowing in cognitive speed accounted for the deficit in recall and recognition of the low-frequency words relative to a healthy control group. Depressed mood was significantly associated with recognition of the low-frequency words. Neither processing speed nor depressed mood was associated with storage efficiency. It is concluded that both cognitive speed slowing and depressed mood impact on effortful encoding processes.

Schizophrenia: more evidence for less glutamate.

Evaluation of: Hahn CJ, Hoau-Yan W, Dan-Sung C et al. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat. Med. 12, 824-828 (2006). Schizophrenia may be associated with deficits in glutamate transmission at the N-methyl-D-aspartate (NMDA) receptor complex. Recent work has shown that neuregulin 1 (NRG1) acts via ErbB4 receptors to inhibit NMDA receptor currents. This is important given that NRG1 is a convincing susceptibility gene in schizophrenia. Hahn and colleagues add to our knowledge of NRG1 modulation of NMDA receptors and show intriguing differences between control and schizophrenic brains. NMDA receptors in the schizophrenic prefrontal cortex showed smaller responses to exogenously applied NMDA/glycine. Furthermore, NMDA receptors in tissue from schizophrenic patients appeared to be more sensitive to the inhibitory effects of a fixed dose of NRG1. In agreement, the ErbB4-PSD-95-NMDA complex was more tightly coupled in schizophrenic brains and NRG1-mediated stimulation of ErbB4 was markedly enhanced. These findings underscore the importance of NMDA receptors in schizophrenia and support therapeutic strategies aimed at boosting glutamate transmission.

The relationship between prolactin levels and glucose homeostasis in antipsychotic-treated schizophrenic patients.

OBJECTIVES: To determine if prolactin levels are associated with glucose-insulin homeostasis in antipsychotic-treated patients with schizophrenia. METHOD: Prolactin levels and glucose homeostasis (quantified using oral glucose tolerance testing, insulin measurement, and homeostasis model assessment) were measured in 15 patients with elevated prolactin levels secondary to antipsychotic treatment of schizophrenia (mean age, 30.4 years; SD, 5.3 years). The effect of reducing prolactin levels by switching patients' antipsychotic treatment to clozapine was ascertained by performing the measures before and after the switch to clozapine. RESULTS: There was no significant correlation between prolactin and glucose-insulin measures at baseline. There was a large reduction in prolactin (593 mIU/L) after switching to clozapine, but this was not associated with changes in glucose-insulin measures. CONCLUSIONS: Prolactin is not a significant determinant of glucose-insulin homeostasis in patients taking antipsychotics for schizophrenia. There was no benefit from lowering prolactin levels using clozapine. This could be because prolactin does not have a major effect on glucose homeostasis or that the effects of prolactin reduction are countered by clozapine.

Towards NR2B receptor selective imaging agents for PET-synthesis and evaluation of N-[11C]-(2-methoxy)benzyl (E)-styrene-, 2-naphthyl- and 4-trifluoromethoxyphenylamidine.

Three potent and selective 11C-labelled NR2B antagonists have been synthesized and evaluated as PET ligands. The brain uptake of the compounds in mice varied substantially and was dominated by metabolism. One compound was found to have favourable uptake and retention in the brain, as well as a binding pattern consistent with the expression of the target receptor as measured by in vitro autoradiography. However, the metabolism of the compounds tested was too rapid to allow for in vivo imaging.

[123I]TPCNE--a novel SPET tracer for the sigma-1 receptor: first human studies and in vivo haloperidol challenge.

[123I]TPCNE (1(trans-[123I]iodopropen-2-yl)-4-[(4-cyanophenoxy)methyl] piperidine; Ki = 0.67 nM; log P = 3.36) is a novel sigma-1 receptor SPET ligand. In this study, we developed an optimized labeling method for [123I]TPCNE and investigated the kinetics, binding characteristics, and whole-body distribution of this tracer for the first time in humans. We also performed a challenge with the sigma-1 receptor antagonist haloperidol against [123I]TPCNE. Seven healthy volunteers were recruited. Dynamic brain SPET scans were performed following i.v. administration of 185 MBq [123I]TPCNE in all seven subjects. Three of the subjects were given oral haloperidol (2.5 mg) approximately 1 h before the scan. The dynamic data were analyzed with both reversible and irreversible compartmental models.[123I]TPCNE showed high uptake in brain and liver. All non-haloperidol-treated subjects showed a high whole-brain uptake (average: 8.7% of injected activity). No significant clearance of the tracer was seen up to 30 h post injection. In the haloperidol-treated subjects, the time-activity curves clearly demonstrated clearance of the tracer from the brain. Regional radioactivity concentrations were reduced by haloperidol from 42% in the cerebellum to 73% in the thalamus.[(123)I]TPCNE demonstrated high brain uptake, with highest binding found in the posterior cingulate. A region in which binding was unaffected by haloperidol pretreatment could not be identified, and the time-activity data were best described by an irreversible model.

Processing speed: a strong predictor of verbal memory performance in schizophrenia.

The role of slowing of processing speed in verbal memory impairment in patients with schizophrenia was investigated. Forty-one patients with schizophrenia and 41 healthy control subjects were administered a verbal memory task involving free recall of three lists of words, which varied in their degree of semantic organization. Standard processing speed tests were administered as well. Regression analyses were conducted on the number of words recalled in each list. A global processing speed measure was a significant predictor of the recall of each list in patients. Patients were very significantly impaired in the recall of the three lists relative to healthy controls. However, when the processing speed measure was entered in the regression, the significance of diagnosis was considerably reduced for one of the lists, with no semantic organization, and eliminated for the other two lists which contained semantic organization. These findings suggest that slowing in processing speed is an important contributor to verbal memory impairment in patients with schizophrenia. The possible role of various specific slowing functions is discussed.