Decreases In Positive Symptoms Research Articles

History of tobacco smoking and alcohol use can predict the effectiveness of electroconvulsive therapy in individuals with schizophrenia: A multicenter clinical trial

BackgroundCurrent research has found that factors such as gender, age, and family history can predict the efficacy of electroconvulsive therapy (ECT) in individuals with schizophrenia. In our clinical practice, we anecdotally observed that tobacco smokers and alcohol drinkers with schizophrenia seemed to respond more effectively to ECT than non-smokers and non-drinkers. The current study aimed to examine whether history of tobacco smoking or alcohol consumption serve as indicators for predicting therapeutic efficacy of ECT in individuals with schizophrenia. MethodsA total of 481 individuals receiving ECT combined with antipsychotic medication (ECT + AP medication) completed a two-week (six sessions of ECT) follow-up; 106 individuals receiving only antipsychotic medication (AP medication) also completed a two-week follow-up. Smoking, alcohol consumption, and AP medication usage was recorded for these individuals. Severity of psychotic symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). ResultsECT + AP medication: Compared to schizophrenic individuals without a history of smoking (non-smokers), those with a history of smoking (smokers) showed a high decrease in negative symptoms (36.96% vs 24.76%; F = 5.974, p = 0.015). While, compared to individuals without a history of alcohol consumption (non-drinkers), those with a history of alcohol consumption (drinkers) showed a high decrease in positive symptoms (48.90% vs 41.47%; F = 5.074, p = 0.025). AP medication: No differences were found in symptom reduction between smokers and non-smokers or between drinkers and non-drinkers (p > 0.05). ConclusionsSmoking history in schizophrenic individuals independently predicts better improvement in negative symptoms after ECT, while alcohol consumption history independently predicts better improvement in positive symptoms after ECT. This is a clinically significant finding.

Cognitive functions following initiation of antipsychotic medication in adolescents and adults at clinical high risk for psychosis: a naturalistic sub group analysis using the MATRICS consensus cognitive battery

BackgroundThe effects of antipsychotic (AP) medications on cognitive functions in individuals at clinical high-risk (CHR) of psychosis are poorly understood. This study compared the effects of AP treatment on cognitive improvement in CHR adolescents and adults.MethodsA total of 327 CHR participants, with an age range of 13 to 45 years, who underwent baseline neuropsychological assessments and a 1-year clinical follow-up were included. Participants with CHR were categorized into four groups based on their age: adolescents (aged < 18) and adults (aged ≥ 18), as well as their antipsychotic medication status (AP+ or AP−). Therefore, the four groups were defined as Adolescent-AP−, Adolescent-AP+, Adult-AP−, and Adult-AP+.ResultsDuring the follow-up, 231 CHR patients received AP treatment, 94 converted to psychosis, and 161 completed the 1-year follow-up. The Adolescent-AP+ group had more positive symptoms, lower general functions, and cognitive impairments than the Adolescent-AP− group at baseline, but no significant differences were observed among adults. The Adolescent-AP+ group showed a significant increase in the risk of conversion to psychosis (p < 0.001) compared to the Adolescent-AP− group. The Adult-AP+ group showed a decreasing trend in the risk of conversion (p = 0.088) compared to the Adult-AP− group. The Adolescent-AP− group had greater improvement in general functions (p < 0.001), neuropsychological assessment battery mazes (p = 0.025), and brief visuospatial memory test-revised (p = 0.020), as well as a greater decrease in positive symptoms (p < 0.001) at follow-up compared to the Adolescent-AP+ group. No significant differences were observed among adults.ConclusionsEarly use of AP was not associated with a positive effect on cognitive function in CHR adolescents. Instead, the absence of AP treatment was associated with better cognitive recovery, suggesting that AP exposure might not be the preferred choice for cognitive recovery in CHR adolescents, but may be more reasonable for use in adults.

“God speaks to me through a dove”. The evidence of clozapine in treatment-refractory psychosis

IntroductionClozapine is an atypical antipsychotic synthesised in 1958. It was withdrawn from the market in the 1970s due to the appearance of agranulocytosis, but was reintroduced due to strong evidence of its efficacy and superiority over other antipsychotics in treatment-resistant schizophrenia.ObjectivesTo describe the adequate response to clozapine in treatment-refractory psychosis.MethodsReview of the scientific literature based on a relevant clinical case.ResultsA 16-year-old woman was admitted to a psychiatric inpatient unit for psychotic symptoms and behavioural disorders. She lives with her father and older sister; she has not been in contact with her mother, who lives in another country, for several years. She attends secondary school, with poor academic performance. Maternal diagnosis of schizophrenia. She started using cannabis two years ago, with a progressive increase up to 20 grams per week. He reports the onset of a feeling of strangeness a year ago, with progressive isolation in his room, referring to delirious ideation of harm towards classmates and people from his town, self-referentiality and delirious interpretations of religious mystical content (“God speaks to me through a dove”). He comments on the phenomenon of theft and thought-reading. Soliloquies and unmotivated laughter are observed.ConclusionsTreatment was started with risperidone, progressively increasing the dose up to optimisation, without achieving a decrease in positive symptoms, but with the appearance of excessive sedation and sialorrhoea. It was combined with aripiprazole up to 20mg, maintained for a couple of weeks, without significant clinical improvement. Given the failure of two lines of therapy, it was decided to change to clozapine up to a dose of 75mg, with adequate tolerance and response, achieving a distancing of the delirious ideation. Regular haematological controls were performed, with no alterations in haemogram or troponins.Disclosure of InterestNone Declared

Feasibility and Effect of Increasing Clozapine Plasma Levels in Long-Stay Patients With Treatment-Resistant Schizophrenia

It is unknown whether increasing the clozapine plasma level to 400, 750, or even 1000 ng/mL is a feasible and effective strategy in patients with treatment-resistant schizophrenia (TRS). We investigated this in long-stay patients with TRS. In long-stay TRS patients, doses of clozapine were increased gradually to reach target plasma levels of 400, 750, or 1000 ng/mL, depending on the clinical response and tolerability. After an effective or tolerated level was reached, positive and negative syndrome scale scores were evaluated after 3 months and 1 year. Twenty-eight patients were included. Overall, 54% of the patients, and especially patients 60 years and older, could not achieve one of the clozapine target levels because of adverse effects. Three physically vulnerable patients died, probably not directly related to clozapine use. Although only 21% of patients achieved a more than 20% reduction in total symptoms at the 1-year follow-up, the mean severity of positive symptoms decreased from 18.18 to 15.10 ( P < 0.01). The largest decrease in positive symptoms was seen in TRS patients who achieved a plasma level of 750 ng/mL of clozapine. Most TRS patients older than 60 years could not tolerate high clozapine levels and so this should not be attempted in older or otherwise physically vulnerable patients. Increasing clozapine levels to approximately 750 ng/mL in middle-aged patients with longstanding TRS may modestly reduce the severity of positive symptoms and improve the response rate.

Sense of self and psychosis, part 2: A single case study on amniotic therapy

Some people diagnosed with schizophrenia show an alteration of the sense of self. From a psychodynamic perspective, it has been hypothesized they have disorders of the integration of self/other identification/differentiation processes. From a neuroscientific view some with this diagnosis present dysfunctions in neural correlates of representation of self from other (the implicit sensorimotor-based bodily self), and self united with other. In “Sense of self and psychosis, part 1” we discussed scientific literature offering empirical evidence for the psychodynamic clinical observations that patients with diagnoses of psychoses didn't receive adequate early infancy parental care and sufficient affective-sensorial/tactile interactions. Introducing parental care/cutaneous interactions seemed relevant in the analytic treatment of psychoses, as the pioneers of the psychoanalytic approach to psychosis suggested. From this theoretical basis we developed amniotic therapy, which reproduces the affective-tactile interactions of early infancy, insufficient in cases of psychosis, and aims at integrating the processes of differentiation and identification. We present a single case study of an experimental intervention plan including amniotic therapy. Results showed increases in interoception and global functioning, with significant decreases in positive symptoms suggesting that amniotic therapy contributes to increasing the protective strength of self-boundaries and integration of identification/differentiation processes.

Effects of Metacognitive Training on Cognitive Insight in a Sample of Patients with Schizophrenia.

Metacognitive training (MCT) is a group intervention that addresses cognitive biases and distortions that could help maintain delusions and hallucinations in people with schizophrenia. This program has proven its effectiveness in reducing the symptoms, but its impact on cognitive insight has scarcely been investigated. Therefore, the aim of the study was to assess the program’s impact on cognitive insight in patients with long-term schizophrenia. A sample of 22 patients with schizophrenia was divided into two groups: one received 16 sessions of MCT (n = 11), while the other received the usual treatment (n = 11). They were assessed using the Beck Cognitive Insight Scale which measures two components, self-reflection and self-certainty, and the Positive and Negative Syndrome Scale (PANSS). The experimental group showed high levels of adherence, an increase in self-reflection, and a decrease in self-assurance levels as hypothesized. We found statistically significant differences between the control and experimental groups in excitation, hostility, positive symptomatology total score, hallucinatory behavior, and suspicion. In the usual treatment group, a non-significant decrease in positive symptoms was also observed. The findings showed that the implementation of the MCT program in real clinical settings can contribute to an improvement in the metacognitive ability and symptomatology of people with schizophrenia.

Who will benefit from computerized cognitive remediation therapy? Evidence from a multisite randomized controlled study in schizophrenia.

Computerized cognitive remediation therapy (CCRT) is generally effective for the cognitive deficits of schizophrenia. However, there is much uncertainty about what factors mediate or moderate effectiveness and are therefore important to personalize treatment and boost its effects. In total, 311 Chinese inpatients with Diagnostic and Statistical Manual of Mental Disorders-IV schizophrenia were randomized to receive CCRT or Active control for 12 weeks with four to five sessions per week. All participants were assessed at baseline, post-treatment and 3-month follow-up. The outcomes were cognition, clinical symptoms and functional outcomes. There was a significant benefit in the MATRICS Consensus Cognitive Battery (MCCB) total score for CCRT (F1,258 = 5.62; p = 0.02; effect size was 0.27, 95% confidence interval 0.04-0.49). There were no specific moderators of CCRT improvements. However, across both groups, Wisconsin Card Sort Test improvement mediated a positive effect on functional capacity and Digit Span benefit mediated decreases in positive symptoms. In exploratory analyses younger and older participants showed cognitive improvements but on different tests (younger on Symbol Coding Test, while older on the Spatial Span Test). Only the older age group showed MSCEIT benefits at post-treatment. In addition, cognition at baseline negatively correlated with cognitive improvement and those whose MCCB baseline total score was around 31 seem to derive the most benefit. CCRT can improve the cognitive function of patients with schizophrenia. Changes in cognitive outcomes also contributed to improvements in functional outcomes either directly or solely in the context of CCRT. Age and the basic cognitive level of the participants seem to affect the cognitive benefits from CCRT.

A Case of Chronic Schizophrenia Who were Switched from Combined Treatment to Monotherapy and Achieved a Decrease in Positive Symptoms after Lowering the Clozapine Dose

ABSTRACTDespite the limited evidence to support the combination of antipsychotics in treatment resistant schizophrenia in the literature, this situation is common in clinical practice. Treatment guidelines recommend monotherapy for schizophrenia primarily. In this article, a chronic schizophrenic case whose treatment is changed from combination of clozapine with aripiprazole to clozapine monotherapy and whose positive symptoms decreased with the decrease of clozapine doses 900 mg/day to 625 mg/day is reported.

P.3.d.011 Reasons for aripiprazole discontinuation – a retrospective review

The traditional antipsychotics are generally poorly effective or ineffective against the negative symptoms of schizophrenia and are also associated with extensive side effects which can themselves cause or exacerbate secondary negative symptomatology. As well as having a low propensity to cause extrapyramidal side effects (EPS), the currently available, putative, atypical antipsychotics (clozapine, risperidone, sertindole, and olanzapine), developmental antipsychotics (zotepine, quetiapine and ziprasidone) and low doses of certain traditional antipsychotics, such as amisulpride and fluphenazine, have been reported to ameliorate negative symptoms in comparison with placebo or standard antipsychotics such as fluphenazine, haloperidol or perphenazine. To date, few trials have specifically examined primary negative symptomatology and it has been suggested that the improvements observed with these drugs may be related to decreases in positive symptoms and/or reduced sedation or extrapyramidal side effects. Although atypicality has been ascribed to 5-HT2/D2 antagonism, the exact pharmacological mechanism(s) underlying the efficacy of the atypical antipsychotics have not been elucidated. Many of these drugs bind to multiple other receptors and/or inhibit neurotransmitter uptake and it seems probable that some of these other pharmacological properties may also contribute to their clinical features.

Combining computerized social cognitive training with neuroplasticity-based auditory training in schizophrenia.

Social cognitive deficits are an important treatment target in schizophrenia, but it is unclear to what degree they require specialized interventions and which specific components of behavioral interventions are effective. In this pilot study, we explored the effects of a novel computerized neuroplasticity-based auditory training delivered in conjunction with computerized social cognition training (SCT) in patients with schizophrenia. Nineteen clinically stable schizophrenia subjects performed 50 hours of computerized exercises that place implicit, increasing demands on auditory perception, plus 12 hours of computerized training in emotion identification, social perception, and theory of mind tasks. All subjects were assessed with MATRICS-recommended measures of neurocognition and social cognition, plus a measure of self-referential source memory before and after the computerized training. Subjects showed significant improvements on multiple measures of neurocognition. Additionally, subjects showed significant gains on measures of social cognition, including the MSCEIT Perceiving Emotions, MSCEIT Managing Emotions, and self-referential source memory, plus a significant decrease in positive symptoms. Computerized training of auditory processing/verbal learning in schizophrenia results in significant basic neurocognitive gains. Further, addition of computerized social cognition training results in significant gains in several social cognitive outcome measures. Computerized cognitive training that directly targets social cognitive processes can drive improvements in these crucial functions.

L-lysine as adjunctive treatment in patients with schizophrenia: a single-blinded, randomized, cross-over pilot study

BackgroundAccumulating evidence suggests that the brain's nitric oxide (NO) signalling system may be involved in the pathophysiology of schizophrenia and could thus constitute a novel treatment target. The study was designed to investigate the benefit of L-lysine, an amino acid that interferes with NO production, as an add-on treatment for schizophrenia.MethodsL-lysine, 6 g/day, was administered to 10 patients with schizophrenia as an adjunctive to their conventional antipsychotic medication. The study was designed as a single-blinded, cross-over study where patients were randomly assigned to initial treatment with either L-lysine or placebo and screened at baseline, after four weeks when treatment was crossed over, and after eight weeks.ResultsL-lysine treatment caused a significant increase in blood concentration of L-lysine and was well tolerated. A significant decrease in positive symptom severity, measured by the Positive And Negative Syndrome Scale (PANSS), was detected. A certain decrease in score was also observed during placebo treatment and the effects on PANSS could not unequivocally be assigned to the L-lysine treatment. Furthermore, performance on the Wisconsin Card Sorting Test was significantly improved compared to baseline, an effect probably biased by training. Subjective reports from three of the patients indicated decreased symptom severity and enhanced cognitive functioning.ConclusionsFour-week L-lysine treatment of 6 g/day caused a significant increase in blood concentration of L-lysine that was well tolerated. Patients showed a significant decrease in positive symptoms as assessed by PANSS in addition to self-reported symptom improvement by three patients. The NO-signalling pathway is an interesting, potentially new treatment target for schizophrenia; however, the effects of L-lysine need further evaluation to decide the amino acid's potentially beneficial effects on symptom severity in schizophrenia.Trial registrationNCT00996242

Prognostic value of duration of untreated psychosis in long-term outcome of schizophrenia

SummaryBackgroundThe goal of this prognostic study was to investigate whether the duration of untreated psychosis (DUP) may have a prognostic value with regard to the further course of the illness.Material/MethodsFifty-eight patients (77% of the original study group) diagnosed with DSM III schizophrenia and later re-diagnosed with DSM IV T-R were assessed at 4 time points. Number of relapses, average time of inpatient treatment, number of inpatient readmissions, and severity of psychopathological symptoms were assessed at 1-, 3-, 7- and 12-year follow-ups. DUP information was obtained by clinical interview with patients and their families. The severity of symptoms was assessed using BPRS-SA, UCLA version.ResultsIncreases in the number of relapses at follow-ups were more prominent in the group with a longer DUP (p<0.001). Decreases in the results of BPRS (symptom improvement) were more prominent in patients with a shorter DUP. The latter had significantly lower results than patients with a long DUP at each assessment except the index hospitalization (p equalled, respectively: 0.449; 0.002; 0.012; 0.034 and 0.014). Decreases in positive symptoms were greater in patients with a short DUP – significant at all except the 7-year follow-up (p equalled respectively: 0.230; <0.001; 0.011; 0.214; <0.001).Conclusions1) A positive correlation was found between DUP and the dynamics of general and positive symptoms and the number of relapses. 2) There was no significant relationship between DUP and the dynamics of negative symptoms, whereas the relationship between the time and number of re-hospitalizations was marginally significant.

An fMRI study of prefrontal dysfunction and symptomatic recovery in schizophrenia

Prefrontal cortical dysfunction has been implicated in the pathophysiology of schizophrenia but it is unclear to what extent these are related to changes in symptomatology as well as task demand. We examined the neural correlates of symptom change and task demand during a longitudinal functional magnetic resonance imaging (fMRI) study using a verbal fluency task with differential task demands in patients with schizophrenia and matched healthy control subjects. The fMRI data were acquired using clustered acquisition technique, enabling ongoing monitoring of behavioural responses, in the patient group on two occasions separated by 6-8 weeks, and the control group at baseline. Positive psychotic symptoms were significantly reduced over the 6-8-week duration of the study. This change was associated with increased activation within the left middle frontal gyrus and decreased activation of the left precuneus. An interaction between symptom change and task demand was evident in the activation of the left middle frontal gyrus. The decrease in positive symptoms was associated with normalisation of activation in the dorsolateral prefrontal cortex and a decrease in parietal activation during the verbal fluency task. The data supports the role of dysfunctional prefronto-parietal relationships in the genesis of positive psychotic symptoms.

Evolution of symptoms with antipsychotic treatment in schizophrenic outpatients in Greece: the GRACE Study

In total, 2013 patients, mean age 39.7 ± 12.5, were included in the study, 54.4% of which were males and 45.6% females. Most of the patients were unmarried (64%), living with their family (64.4%) and unemployed (54.2%) at the time of screening. After treatment change to another antipsychotic agent positive symptoms significantly decreased by 23.6% (p < 0.005), negative symptoms remained unchanged and other symptoms significantly decreased by 15.9% (p < 0.05). Illusions, delusions and disorganised speech/thinking, were the positive symptoms with the most profound decrease (14% p < 0.001, 13.1% p < 0.001 and 5.4% p < 0.005 respectively). No significant changes were observed in affective flattening, aggressiveness, sleep and cognitive disorders. All administered antipsychotic treatments were associated with significant decrease in positive symptoms, with ziprasidone, olanzapine, rispesridone, quetiapine, aripiprazole, and aminosulpride showing more than 20% decrease (p < 0.001). Ziprasidone, aripiprazole, cloazapine, quetiapine and aminisulrpide were associated with decrease in negative treatments, however only ziprasidone and ariprazole decreases reached significance (p < 0.01 and p < 0.02 respectively. All agents, showed significant decrease in other symptoms (p < 0.001).

Using the Stroop task to investigate the neural correlates of symptom change in schizophrenia

This study examined brain activation during a cognitive inhibition task in patients with schizophrenia following changes in their positive symptoms. A Stroop task was used during functional magnetic resonance imaging in 11 patients with schizophrenia (patient group) and 9 healthy volunteers (control group). At baseline, the patient group showed significantly attenuated activation within the anterior cingulate gyrus, left pre-/postcentral gyrus and inferior frontal junction. At follow-up, there was a significant increase in activation in the left inferior frontal junction associated with a decrease in positive symptoms, suggesting this region plays a role in the development of these symptoms.

USING THE STROOP TASK TO INVESTIGATE THE NEURAL CORRELATES OF SYMPTOM CHANGE IN SCHIZOPHRENIA

This study examined brain activation during a cognitive inhibition task in patients with schizophrenia following changes in their positive symptoms. A Stroop task was used during functional magnetic resonance imaging in 11 patients with schizophrenia (patient group) and 9 healthy volunteers (control group). At baseline, the patient group showed significantly attenuated activation within the anterior cingulate gyrus, left pre-/postcentral gyrus and inferior frontal junction. At follow-up, there was a significant increase in activation in the left inferior frontal junction associated with a decrease in positive symptoms, suggesting this region plays a role in the development of these symptoms.

Metabolic Correlates of Antidepressant and Antipsychotic Response in Patients With Psychotic Depression Undergoing Electroconvulsive Therapy

Although electroconvulsive therapy (ECT) is a very effective treatment of depression and psychosis, the mechanisms by which this occurs are not fully delineated. The objective of this study was to investigate the functional alterations in brain metabolism in response to ECT through the use of positron emission tomography assessment of cerebral glucose metabolism before and after a course of ECT. Ten subjects with psychotic depression were studied with positron emission tomography using [F]fluorodeoxyglucose before and between 2 and 3 weeks after a course of ECT. Statistical parametric mapping and region of interest analyses of the anterior cingulate cortex (ACC) subregions (dorsal, rostral, subcallosal, and subgenual) and hippocampus were used to determine glucose metabolic changes from ECT. The Hamilton Depression Rating Scale and the Scale for Assessing Positive Symptoms were the primary measures used for assessing clinical changes from ECT. Electroconvulsive therapy led to significant increases in the left subgenual ACC and hippocampal metabolism, which were directly correlated with each other and to a reduction in depression as measured by total Hamilton Depression Rating Scale scores. Better antidepressant responders had increased, whereas poorer responders had a decreased left subgenual ACC and hippocampal metabolism. The decrease in positive symptoms was also correlated with increased left hippocampal metabolism. The antidepressant effect of ECT was correlated with increased metabolism in the left subgenual ACC and hippocampus, whereas the antipsychotic effect of ECT was only correlated with increased left hippocampal metabolism. This finding has implications to better understand the mechanism of antidepressant and antipsychotic effects of ECT.

Lifelong Course of Positive and Negative Symptoms in Chronically Institutionalized Patients with Schizophrenia

Background: Despite widespread policies of deinstitutionalization, a substantial number of patients with schizophrenia require continuous custodial care. The hospital records of such patients provide contemporaneous documentation of symptoms throughout the illness, permitting a longitudinal study of the course of symptoms. We sought to describe this course, and to determine the influences of sex, age of onset, and treatment on its evolution. Methods: Using the modified Diagnostic Evaluation After Death, we performed standardized chart reviews of 99 chronic inpatients who remained in state institutions through the 1960’s and 1970’s and subsequently died in those institutions. Data were available from the onset of illness until death. Results: We found significant decreases in positive symptoms and increases in negative symptoms over the course of the illness. Symptom patterns were analyzed by repeated measures ANOVA. Onset before age 25 was associated with greater numbers of negative symptoms at a given age (p = 0.05). Female sex was associated with greater numbers of positive symptoms (p = 0.04). The widespread introduction of neuroleptic drugs in the mid-1950’s did not affect the trends in symptom patterns. Conclusions: The lifetime course of schizophrenia in chronically institutionalized individuals is characterized by a decrease in positive symptoms and an increase in negative symptoms. Schizophrenia with earlier onset is associated with greater numbers of negative symptoms throughout life. In this sample of patients, chronically hospitalized until death, neuroleptic drugs failed to effect a persistent decrease in positive symptoms.

Dose-response analysis of first- and second-generation antipsychotics

The traditional antipsychotics are generally poorly effective or ineffective against the negative symptoms of schizophrenia and are also associated with extensive side effects which can themselves cause or exacerbate secondary negative symptomatology. As well as having a low propensity to cause extrapyramidal side effects (EPS), the currently available, putative, atypical antipsychotics (clozapine, risperidone, sertindole, and olanzapine), developmental antipsychotics (zotepine, quetiapine and ziprasidone) and low doses of certain traditional antipsychotics, such as amisulpride and fluphenazine, have been reported to ameliorate negative symptoms in comparison with placebo or standard antipsychotics such as fluphenazine, haloperidol or perphenazine. To date, few trials have specifically examined primary negative symptomatology and it has been suggested that the improvements observed with these drugs may be related to decreases in positive symptoms and/or reduced sedation or extrapyramidal side effects. Although atypicality has been ascribed to 5-HT2/D2 antagonism, the exact pharmacological mechanism(s) underlying the efficacy of the atypical antipsychotics have not been elucidated. Many of these drugs bind to multiple other receptors and/or inhibit neurotransmitter uptake and it seems probable that some of these other pharmacological properties may also contribute to their clinical features.

Drug treatment of the negative symptoms of schizophrenia

The traditional antipsychotics are generally poorly effective or ineffective against the negative symptoms of schizophrenia and are also associated with extensive side effects which can themselves cause or exacerbate secondary negative symptomatology. As well as having a low propensity to cause extrapyramidal side effects (EPS), the currently available, putative, atypical antipsychotics (clozapine, risperidone, sertindole, and olanzapine), developmental antipsychotics (zotepine, quetiapine and ziprasidone) and low doses of certain traditional antipsychotics, such as amisulpride and fluphenazine, have been reported to ameliorate negative symptoms in comparison with placebo or standard antipsychotics such as fluphenazine, haloperidol or perphenazine. To date, few trials have specifically examined primary negative symptomatology and it has been suggested that the improvements observed with these drugs may be related to decreases in positive symptoms and/or reduced sedation or extrapyramidal side effects. Although atypicality has been ascribed to 5-HT 2/D 2 antagonism, the exact pharmacological mechanism(s) underlying the efficacy of the atypical antipsychotics have not been elucidated. Many of these drugs bind to multiple other receptors and/or inhibit neurotransmitter uptake and it seems probable that some of these other pharmacological properties may also contribute to their clinical features.