Neurological soft signs and their relationship to cognitive and clinical efficacy of atypical antipsychotics in schizophrenia.

Neurological soft signs (NSS) are nonspecific indicators of brain dysfunction that are found to be in excess and correlated with cognitive dysfunction and psychopathology in patients with schizophrenia. The aim of the study was to examine whether the severity of NSS determines the efficacy of atypical antipsychotics in schizophrenia. Forty-three patients with schizophrenia were assessed on psychopathology and cognitive domains of executive functioning, memory, attention, and psychomotor speed at baseline and 6 months after they had been switched from typical to atypical antipsychotics. NSS were examined at baseline. The high-NSS group showed more severe psychopathology and greater impaired cognitive function than the low-NSS group at baseline. Following treatment, there were improvements in cognitive functioning and psychopathology with the low-NSS group, which showed significant improvements on measures of verbal fluency, memory, and psychomotor speed and negative symptoms. The high-NSS group also showed improvements on most of these measures, but the improvement was less than that seen in the low-NSS group. The presence of high NSS in schizophrenia patients impedes the improvement in cognitive function with atypical antipsychotics treatment.

Cognitive effects of olanzapine and clozapine treatment in chronic schizophrenia.

RATIONALE: Schizophrenia patients are known to manifest widespread, multifaceted cognitive deficits. There is now an increasing emphasis on the critical importance of cognitive deficits for the functional outcome in schizophrenia. Typical antipsychotics, although effective in reducing positive symptoms of the illness, have not shown much effect on cognitive functions. Atypical antipsychotics have shown promise of improving some cognitive functions. OBJECTIVES: This naturalistic study aimed to determine whether olanzapine and clozapine improve cognitive functioning in a sample of 48 patients with chronic schizophrenia who had either failed to show sufficient clinical improvements or suffered from distressing side effects with conventional antipsychotics and were switched to either olanzapine or clozapine for clinical reasons and, if so, whether the two drugs produce similar or different cognitive effects. METHODS: All patients completed a comprehensive battery of neuropsychological tests designed to index executive functioning, verbal learning, verbal and visual and memory, attention, working memory, and psychomotor speed at: (i) baseline, (ii) after 6 weeks and (iii) after 6 months of treatment with olanzapine or clozapine. RESULTS: From the initial 48 patients who remained on olanzapine ( n=16) or clozapine ( n=14) for the entire duration with continuous participation, 30 provided data for this study. There were improvements over time (i.e. from baseline through 6 weeks to 6 months) in both treatment groups on verbal fluency, verbal learning and verbal and visual memory measures. CONCLUSIONS: The findings indicate similar beneficial effects of olanzapine and clozapine on verbal learning and memory measures in patients showing a favourable clinical response to these drugs.

Neural correlates of tactile prepulse inhibition: a functional MRI study in normal and schizophrenic subjects.

Prepulse inhibition (PPI) of the startle reflex refers to the ability of a weak prestimulus, the prepulse, to inhibit the response to a closely following strong sensory stimulus, the pulse. PPI is found to be deficient in a number of psychiatric and neurological disorders associated with abnormalities at some level in the limbic and cortico-pallido-striato-thalamic circuitry. We applied whole-brain functional magnetic resonance imaging to elucidate the neural correlates of PPI using airpuff stimuli as both the prepulse and the pulse in groups of (i) healthy subjects and (ii) schizophrenic patients. Cerebral activation during prepulse-plus-pulse stimuli with stimulus-onset asynchronies of 120 ms was contrasted with activation during pulse-alone stimuli. In healthy subjects, PPI was associated with increased activation bilaterally in the striatum extending to hippocampus and thalamus, right inferior frontal gyrus and bilateral inferior parietal lobe/supramarginal gyrus, and with decreased activation in the right cerebellum and left medial occipital lobe. All activated regions showed significantly greater response in healthy subjects than schizophrenic patients, who also showed a trend for lower PPI. The findings demonstrate involvement of the striatum, hippocampus, thalamus, and frontal and parietal cortical regions in PPI. Dysfunctions in any of these regions may underlie observations of reduced PPI in schizophrenia.

Longitudinal study of symptoms and cognitive function in chronic schizophrenia.

There is conflicting evidence of a relationship between changes in symptoms and cognitive functioning in schizophrenia. This study investigated longitudinal changes in psychopathology and cognitive functioning in chronic schizophrenia utilising three different dimensional models of symptomatology. Sixty-two patients diagnosed with DSM-IV schizophrenia or schizoaffective disorder were examined on two occasions over a period of 6 months for symptom improvement, measured by Positive and Negative Syndrome Scale (PANSS) [Kay et al., Schizophr. Bull. 13 (1987) 261]. Participants also completed a comprehensive battery of neuropsychological tasks designed to assess attention, verbal and non-verbal memory, psychomotor processing and executive/frontal functioning on both occasions. Twenty-five control subjects were assessed for comparison purposes. Severity of negative symptoms predicted poor neuropsychological performance on IQ, verbal fluency and memory measures at occasion one. However, using regression analyses, significant improvements in symptom ratings over time using two-, three- or five-dimensional models did not predict improvements in any aspect of cognitive functioning measured, except motor speed. The results do not suggest a causal relationship between the course of symptoms and neuropsychological functioning in chronic schizophrenia.

Procedural learning in schizophrenia: a functional magnetic resonance imaging investigation.

Procedural learning (PL) is a type of rule-based learning in which performance facilitation occurs with practice on task without the need for conscious awareness. Schizophrenic patients have often (though not invariably) been found to show impaired PL. We performed functional magnetic resonance imaging (fMRI) during a blocked, periodic sequence-learning task with groups of: (i) healthy subjects, and (ii) schizophrenic patients on conventional antipsychotics. Healthy subjects showed significant PL, but patients did not. In healthy subjects, PL was associated with increased activation in the striatum, thalamus, cerebellum, precuneus, medial frontal lobe, and cingulate gyrus. The power of activation in the thalamus, striatum, precuneus, cingulate gyrus and BA 6 was related to the magnitude of PL in these subjects. No regions, except the anterior inferior gyrus, were significantly activated in patients. The caudate nucleus, thalamus, precuneus, and sensorimotor regions were activated significantly differently between the two groups. The findings demonstrate the involvement of the striatum, cerebellum, thalamus, cingulate gyrus, precuneus, and sensorimotor regions in PL. Further fMRI studies of PL in normal subjects treated with conventional antipsychotics, drug naïve patients, and patients given atypical antipsychotics would help to clarify the roles of schizophrenic disease processes and antipsychotic medication in impaired PL and associated brain abnormalities in schizophrenia.

Prepulse inhibition of the startle response in risperidone-treated patients: comparison with typical antipsychotics.

Individuals with schizophrenia are known to show deficits in prepulse inhibition (PPI) of the startle response. PPI refers to a response suppression in reaction to a strong startling stimulus, if preceded briefly by a weak non-startling stimulus and represents a well-established animal model to investigate information processing deficits in schizophrenia. This study examined PPI of the startle acoustic response in schizophrenic patients given typical antipsychotics or a second generation atypical antipsychotic, risperidone, using a naturalistic between-subjects design. Two groups of male schizophrenic patients: (i) stable on a range of typical antipsychotics (n = 20), and (ii) stable on risperidone (n = 10) were tested for PPI (prepulse-to-pulse intervals: 30, 60, and 120 ms, prepulses 15 dB above the background) of the acoustic startle response, and compared with a group of healthy male subjects (n = 20). Patients on typical antipsychotics showed significantly less PPI with 30 and 60 ms prepulse trials than healthy subjects. Risperidone-treated patients did not differ from healthy subjects for PPI with any prepulse trials. Further longitudinal within-subject studies are now required to examine whether risperidone is superior to typical antipsychotics in improving information processing functions, as assessed by PPI of the acoustic startle response, in treatment-responsive male patients with schizophrenia.

Influence of cigarette smoking on prepulse inhibition of the acoustic startle response in schizophrenia.

The prevalence of tobacco smoking is known to be higher in patients with schizophrenia than other psychiatric disorders and general population. These patients also show reduced prepulse inhibition (PPI) of the startle response. PPI refers to a reduction in response to a strong startling stimulus if preceded shortly by a stimulus of sub-threshold intensity. PPI is thought of as an objective index of sensorimotor gating. Nicotine administered subcutaneously or via cigarette smoking enhances PPI in healthy human beings. It also enhances PPI at low, but not high, doses in the rat. We examined the influence of smoking on PPI of the acoustic startle response in 46 male patients with chronic schizophrenia. In a naturalistic design, patients (n = 9) who smoked a cigarette less than 10 min prior to being tested on PPI were compared with other smoking (n = 23) and non-smoking patients (n = 14). We found that the group of patients who smoked a cigarette prior to being tested had significantly greater PPI than other two groups. These observations suggest a PPI-enhancing effect of cigarette smoking on PPI in patents with schizophrenia. Higher prevalence of cigarette smoking in schizophrenic patients may reflect an attempt to improve sensorimotor gating deficits. Copyright 2001 John Wiley & Sons, Ltd.