Impact of catechol-O-methyltransferase on prefrontal brain functioning in schizophrenia spectrum disorders.

The enzyme catechol-O-methyltransferase (COMT) has attracted increasing interest regarding a genetic disposition towards schizophrenias and as a modulator of prefrontal brain function. A common SNP in the COMT gene causes a Val to Met transition at AA158/AA108 (Val158Met), resulting in reduced COMT activity in Met allele carriers. An impact of COMT genotype on cognition has been well established; however, the exact nature of this influence has yet to be elucidated. The aim of this study was to determine whether COMT genotype affects an electrophysiological marker of prefrontal activation and neuropsychological frontal lobe measures in schizophrenia. To this end, 56 acutely psychotic in-patients with schizophrenia spectrum disorders were investigated. Patients with the COMT 1947AA (Met/Met) genotype (n=13) were compared to a carefully matched sample of patients with a G1947A (Val/Met) genotype (n=15); matching criteria included patients' age, handedness, gender distribution, diagnosis, and medication status. A small group of six homozygous Val allele carriers was additionally included to allow an assessment of possible gene-dosage effects. P300 amplitudes and latencies, as well as an electrophysiological marker of prefrontal brain function (NoGo-Anteriorization/NGA) and neuropsychological measures (Stroop Test, Verbal Fluency, Trail Making Test) were regarded. Homozygous Met allele carriers had significantly increased NGA values and fronto-central Nogo amplitudes compared to patients with at least one Val allele. They also tended to perform better in the Stroop task, as compared to the matched group of Val/Met patients. These results indicate that COMT genotype exerts a strong impact on prefrontal functioning and executive control in schizophrenia spectrum disorders.     

DTNBP1 (dysbindin) gene variants modulate prefrontal brain function in healthy individuals.

DTNBP1 (dysbindin) is one of the several putative schizophrenia genes supported by association, neuroanatomical, and cellular studies. These suggest an involvement of DTNBP1 in the prefrontal cortex and cognitive functions mediated by interaction with neurotransmitter systems, in particular glutamate. The influence of DTNBP1 gene variation on prefrontal brain function at the systemic neurophysiological level, though, has not been characterized. The NoGo-anteriorization (NGA) as an event-related potential (ERP) measure elicited during the continuous performance test (CPT) has been established as a valid neurophysiological parameter for prefrontal brain function in healthy individuals and patients with schizophrenias. In the present study, we therefore investigated the influence of eight dysbindin gene variants on the NGA as a marker of prefrontal brain function in 48 healthy individuals. Two DTNBP1 polymorphisms previously linked to schizophrenia (P1765 and P1320) were found associated with changes in the NGA. Post hoc analysis showing an influence of genetic variation at these loci on the Go centroid and frontal amplitudes suggest that this might be due to modification of the execution of motor processes by the prefrontal cortex. This is the first report on a role of DTNBP1 gene variation for prefrontal brain function at a systemic neurophysiological level in healthy humans. Future studies will have to address the relevance of this observation for patients with schizophrenias.     

Different effects of typical and atypical antipsychotics on grey matter in first episode psychosis: the AESOP study.

Typical antipsychotic drugs act on the dopaminergic system, blocking the dopamine type 2 (D2) receptors. Atypical antipsychotics have lower affinity and occupancy for the dopaminergic receptors, and a high degree of occupancy of the serotoninergic receptors 5-HT2A. Whether these different pharmacological actions produce different effects on brain structure remains unclear. We explored the effects of different types of antipsychotic treatment on brain structure in an epidemiologically based, nonrandomized sample of patients at the first psychotic episode. Subjects were recruited as part of a large epidemiological study (AESOP: aetiology and ethnicity in schizophrenia and other psychoses). We evaluated 22 drug-free patients, 32 on treatment with typical antipsychotics and 30 with atypical antipsychotics. We used high-resolution MRI and voxel-based methods of image analysis. The MRI analysis suggested that both typical and atypical antipsychotics are associated with brain changes. However, typicals seem to affect more extensively the basal ganglia (enlargement of the putamen) and cortical areas (reductions of lobulus paracentralis, anterior cingulate gyrus, superior and medial frontal gyri, superior and middle temporal gyri, insula, and precuneus), while atypical antipsychotics seem particularly associated with enlargement of the thalami. These changes are likely to reflect the effect of antipsychotics on the brain, as there were no differences in duration of illness, total symptoms scores, and length of treatment among the groups. In conclusion, we would like to suggest that even after short-term treatment, typical and atypical antipsychotics may affect brain structure differently.     

Pathophysiologic basis for schizophrenia and the efficacy of antipsychotics

Current concepts of schizophrenia and its treatment are discussed. Schizophrenia entails negative symptoms, such as behavioral and cognitive deficits, attributed to loss of normal functions, and positive, or florid, symptoms that originate from the disturbed function of the remainder of the brain. Schizophrenia type I has positive symptoms predominating, and schizophrenia type II has negative symptoms predominating. Many atypical antipsychotics are now in Phase II and Phase III development; the prototype, clozapine, is now available. These agents challenge traditional views about drug treatment in schizophrenia. Schizophrenia may be explained by a persistent impairment in one or more neurotransmitter or neuromodulatory regulatory mechanisms, resulting in unstable or erratic neurotransmission. A more complex conceptualization of the role of the dopaminergic system makes it possible to understand the lack of biochemical tolerance to the therapeutic effects of antipsychotics, the varied time to onset of effects and prevalence of extrapyramidal symptoms, and the differences in efficacy within and among patients. Drug selection on the basis of patient-specific biological markers and neuropsychological function might expedite treatment responses. Drug therapy should augment homeostatic mechanisms and restore appropriate dopaminergic responses to physiological stimuli. Atypical antipsychotics may act by stabilizing presynaptic activity at a new set point, activating prefrontal dopaminergic systems and inhibiting mesolimbic systems, or exerting pharmacologic or functional effects on other neurotransmitter and neuropeptidergic systems. The traditional view that schizophrenia is simply a manifestation of dopaminergic overactivity is inadequate. New investigative techniques and the study of atypical antipsychotics suggest that a dysregulation hypothesis may be more consistent with the complexities of schizophrenia.     

The revised dopamine hypothesis of schizophrenia: evidence from pharmacological MRI studies with atypical antipsychotic medication

The revised dopamine (DA) hypothesis states that clinical symptoms of schizophrenia are caused by an imbalance of the DA system. In this article, we aim to review evidence for this hypothesis by evaluating functional magnetic resonance imaging studies in schizophrenia. Because atypical drugs are thought to have a normalizing effect on DA neurotransmission, we have focused on pharmacological MRI (PhMRI) studies that explore the effect of these drugs on prefrontal and striatal brain activity in schizophrenia patients. We encountered a total of 13 studies, most of which reported enhanced prefrontal activity associated with alleviation of negative symptoms and improvement of cognitive functions, following treatment with atypical antipsychotics. Besides increasing prefrontal cortex activity, atypical antipsychotics have also shown to be effective in the regulation of striatal functioning. The current PhMRI findings support the revised DA hypothesis of schizophrenia by confirming hypoactivity of the prefrontal cortex in schizophrenia and, following atypical antipsychotics, improvement of prefrontal and subcortical functions reflecting enhanced DA activity.     

Olanzapine-induced cerebral metabolic changes related to symptom improvement in schizophrenia

The pattern of brain metabolic changes produced by olanzapine has yet to be described, despite the theoretical and clinical interest of this new antipsychotic. We studied a group of 17 schizophrenic patients who underwent two fluoro-deoxyglucose-positron emission tomography (FDG-PET) studies under two different conditions: a baseline scan during treatment with either conventional antipsychotics (n=15) or risperidone (n=2) and a second scan performed 17-24 weeks after switching to olanzapine. PET scans were obtained while performing a standard cognitive paradigm (Continuous Performance Test) and analysed by means of Statistical Parametric Mapping. No significant metabolic changes were found in the comparison between pre- and post-olanzapine conditions. A brain map of the statistical power of our design showed that changes up to 3% in the frontal and up to 8% in the occipital region were not likely to exist (1-beta=0.8). The degree of improvement in positive symptoms was related to the amount of activity decrease in the right orbital region and to the amount of activity increase in the primary visual area. Improvement in negative symptoms was associated with an activity increase in the dorsal prefrontal cortex, and a higher baseline activity in both temporal poles. These correlation patterns suggest that the functional mechanism of action of olanzapine may share traits from both typical and atypical neuroleptics.     

Chronic phencyclidine (PCP)-induced modulation of muscarinic receptor mRNAs in rat brain: impact of antipsychotic drug treatment

Many antipsychotics (APDs) have a high affinity for muscarinic receptors, which is thought to contribute to their therapeutic efficacy, or side effect profile. In order to define how muscarinic receptor gene expression is affected by atypical or typical APDs, rats were treated with chronic (2.58 mg/kg) PCP (a psychotomimetic) or vehicle, plus clozapine (20 mg/kg/day) or haloperidol (1 mg/kg/day), and M1, M2 and M3 receptor mRNA levels were determined in brain sections. Negligible changes in M2 or M3 muscarinic mRNA were detected in any region after clozapine or haloperidol. Chronic PCP administration increased M1 mRNA expression in the prefrontal cortex, which was not reversed by either chronic clozapine or haloperidol treatment. Chronic clozapine treatment in combination with PCP treatment decreased M1 receptor mRNA levels in the nucleus accumbens core, whereas chronic haloperidol in combination with PCP treatment increased M1 receptor mRNA levels in the ventromedial hypothalamus and medial amygdala. Thus M1 receptor gene expression is targeted by APDs, although the regions affected differ according to the APD treatment and whether PCP has been administered. The different brain circuitry modulated, may reflect the differing modes of action of typical and atypical APDs. These data provide support for the dysregulation of M1 receptors in schizophrenia, and furthermore, modulation by antipsychotic agents in the treatment of schizophrenia.     

长期使用抗精神病药对精神分裂症患者认知功能的影响研究

目的:探讨长期使用典型和非典型抗精神病药对精神分裂症患者认知功能的影响。方法:对45例持续服用典型或非典型抗精神病药10年以上的精神分裂症患者,使用蒙特利尔认知评估量表(MoCA)、简易智能精神状态量表(MMSE)和简明精神病评定量表(BPRS)检测患者目前的认知功能和精神症状。结果:典型和非典型抗精神病药或两型药物联用患者之间的MoCA、MMSE、BPRS差异不显著。结论:长期治疗的精神分裂症患者,认知功能损害与药物因素的相关性不明显,可能与疾病的结局相关。MoCA可作为非急性期精神分裂症患者认知功能的评定工具。     

Brain structural changes associated with chronicity and antipsychotic treatment in schizophrenia

Accumulating evidence suggest a life-long impact of disease related mechanisms on brain structure in schizophrenia which may be modified by antipsychotic treatment. The aim of the present study was to investigate in a large sample of patients with schizophrenia the effect of illness duration and antipsychotic treatment on brain structure. Seventy-one schizophrenic patients and 79 age and gender matched healthy participants underwent brain magnetic resonance imaging (MRI). All images were processed with voxel based morphometry, using SPM5. Compared to healthy participants, patients showed decrements in gray matter volume in the left medial and left inferior frontal gyrus. In addition, duration of illness was negatively associated with gray matter volume in prefrontal regions bilaterally, in the temporal pole on the left and the caudal superior temporal gyrus on the right. Cumulative exposure to antipsychotics correlated positively with gray matter volumes in the cingulate gyrus for typical agents and in the thalamus for atypical drugs. These findings (a) indicate that structural abnormalities in prefrontal and temporal cortices in schizophrenia are progressive and, (b) suggest that antipsychotic medication has a significant impact on brain morphology.     

Impact of legislative changes on patterns of antipsychotic prescribing and self-poisoning in Scotland: 2000-06

Recently, national guidelines have advocated greater use of atypical rather than typical antipsychotics in the treatment of schizophrenia. In addition, there have been safety concerns regarding the potential cardiotoxicity of certain antipsychotics taken in overdose. This has led regulatory authorities in the United Kingdom to restrict the use of thioridazine. The overall impact of these legislative changes on patterns of antipsychotic prescribing has received comparatively little attention. Therefore, we sought to examine the effects on community prescribing practices, and to determine whether this was accompanied by changes in patterns of antipsychotic poisoning. Between 2000-03, there was a rapid decline in the use of typical antipsychotics, whereas the use of atypical antipsychotics increased. The prevalence of atypical and typical antipsychotic prescribing has been approximately equal between 2003-06. During the same study period, hospital admissions due to typical antipsychotic poisoning also declined, however, the effects lagged behind changes in prescribing practice by 2-3 years. These data indicate that legislative changes that restrict the use of thioridazine and other typical antipsychotics are associated with a measurable reduction in the number of hospital admissions due to overdose with these agents.     

Effects of acute versus chronic treatment with typical or atypical antipsychotics on d-amphetamine-induced sensorimotor gating deficits in rats

RATIONALE: Dopamine (DA) receptor agonists disrupt the prepulse inhibition (PPI) in rats which is considered to model PPI deficits observed in schizophrenic patients. Many laboratories have demonstrated that both "typical" and "atypical" antipsychotics reverse the disruptive effect of DA agonists on PPI in rats. These results are based on acute treatment with antipsychotics, which is different from clinical observations since humans receive treatment for months and the effects of antipsychotics only emerge after weeks of treatment. OBJECTIVES: We aimed to investigate the effect of chronic treatment with "typical" and "atypical" antipsychotics on the PPI model in rats. METHODS: We investigated the effect of acute versus sub-chronic (3 days) and chronic (21 days) treatment with haloperidol or two "atypical" antipsychotics (olanzapine; sertindole) on d-amphetamine-disrupted PPI in rats. RESULTS: We observed that all three antipsychotics dose-dependently reversed the disruptive effect of d-amphetamine after acute or sub-chronic treatment, but that this reversal effect disappeared after chronic treatment. We confirmed this effect in the same model using oral administration instead of mini-pumps, and in an additional model predictive of antipsychotic action, i.e. d-amphetamine-induced hyperactivity in rats. CONCLUSIONS: The d-amphetamine-disrupted PPI model highlighted a modification in the effects of antipsychotics after chronic treatment when compared to their acute effects, but only the acute treatment can be considered predictive of antipsychotic action in clinic.     

Combined treatment with atypical antipsychotics and antidepressants in treatment-resistant depression: preclinical and clinical efficacy

Several clinical reports have documented a beneficial effect of adding atypical antipsychotic drugs to ongoing treatments with antidepressants, particularly selective serotonin reuptake inhibitors, in ameliorating drug-resistant depression. The aim of this paper was to summarize some preclinical evidence describing the mechanism responsible for the therapeutic action of combined treatment with antidepressants and atypical antipsychotics and also some clinical data supporting the efficacy and safety of the augmentation strategy for improving antidepressant-resistant depression using atypical antipsychotics. This analysis is based on five microdialysis studies and nine behavioral studies assessing the impact of combined atypical antipsychotic and antidepressant treatments on extracellular levels of dopamine, serotonin and noradrenaline in the prefrontal cortex of freely moving rats and on antidepressant-induced effects, respectively. In addition, clinical data demonstrating the efficacy and safety of augmentation strategies for treatmentresistant depression using atypical antipsychotics were included. Combined treatment of rats with all studied atypical antipsychotics (olanzapine, risperidone, clozapine and quetiapine) and antidepressants (citalopram, fluoxetine and fluvoxamine) increased the extracellular level of dopamine in the prefrontal cortex compared to a respective drug given alone; in addition, a combination of olanzapine or quetiapine plus fluoxetine or fluvoxamine increased the levels of dopamine and noradrenaline. Moreover, atypical antipsychotics administered in a low dose enhanced the antidepressant-like activity of antidepressants, with (among other mechanisms) the serotonin 5-HT_1A, 5-HT_2A and adrenergic a₂ receptors likely playing an important role in their action. The results support the conclusion that atypical antipsychotics may be effective as adjunctive therapy in treatment-resistant depression; however, their adverse effect profile may be unfavorable in some patients.     

Atypical antipsychotics for neuropsychiatric symptoms of dementia: malignant or maligned?

Recent concerns regarding the use of atypical antipsychotics when used for the treatment of neuropsychiatric symptoms in dementia have led to a flurry of studies attempting to re-evaluate their place in therapy. We critically review current evidence on the safety profiles of these agents in patients with behavioural and psychological symptoms of dementia (BPSD) and provide recommendations to guide the clinician. Potential risks with this class of medications include extrapyramidal symptoms (EPS), weight gain, diabetes mellitus, cardiac conduction abnormalities (e.g. corrected QT [QTc] interval prolongation), cerebrovascular adverse events and mortality. Compared with placebo, treatment of BPSD with atypical antipsychotics leads to little or no increase in EPS and no significant weight change. Compared with typical antipsychotics, treatment of BPSD with atypical antipsychotics leads to a reduced risk of EPS, lower incidences of tardive dyskinesias and no significant weight gain. Atypical antipsychotics have not been associated with glucose intolerance, diabetes or hyperlipidaemia in elderly dementia patients. Both typical and atypical antipsychotics have been associated with cardiac conduction abnormalities, with the magnitude of QTc prolongation being slightly smaller with atypical antipsychotics. Randomised controlled trials suggest that atypical antipsychotics are associated with an increased risk of cerebrovascular adverse events, such as stroke, and an increased mortality compared with placebo. However, it appears that typical antipsychotics have similar risks of cerebrovascular adverse events and death. An increased risk of anticholinergic adverse effects and falls must also be considered with both typical and atypical antipsychotics. In summary, atypical antipsychotics are associated with potentially serious adverse events. Before prescribing these medications in elderly dementia patients, baseline EPS, ECG abnormalities and concomitant medications should be assessed, and the presence of cardiovascular, cerebrovascular and metabolic risk factors should be taken into consideration when benefits and risks are being weighed.     

Neuropsychopharmacological study on an animal model for negative symptom of schizophrenia induced by repeated phencyclidine treatment

To develop an animal model for negative symptoms, in particular avolition, of schizophrenia, the effect of phencyclidine (PCP) on immobility (regarded as avolition) in the forced swimming test was investigated in mice, since PCP produces negative symptoms in humans. Unlike single, repeated treatment with PCP prolonged the immobility time in the forced swimming test 24 h after the final injection compared with saline treatment. The enhancing effect of PCP on the immobility persisted for 21 d after the withdrawal of the drug. Atypical antipsychotics attenuated the enhancing effect of PCP on the immobility. Since these attenuating effects were antagonized by a serotonin-S2 receptor agonist, (+/-)-2,5-dimethoxy-4-iodamphetamine (DOI), the effects may be mediated via serotonin-S2 receptors. In contrast with atypical antipsychotics, typical antipsychotics, antidepressants and anxiolytics had no effect. No functional changes in post-synaptic serotonin-S2 receptors were observed in PCP-treated mice following the forced swimming test. Serotonin utilization in the prefrontal cortex was increased, but dopamine utilization was decreased in PCP-treated mice showing the enhancement of immobility. The enhancing effect of PCP was significantly attenuated by D-cycloserine, an agonist for glycine binding site of N-methyl-D-aspartate (NMDA) receptor ionophore complex. Decreases of NMDA receptor function or of the cortical glutamate and glycine levels were observed in PCP-treated mice showing the enhancement of immobility. These results suggest that the enhancing effect of PCP on immobility is mediated by the imbalance of the cortical serotonergic, dopaminergic and glutamatergic systems and could be used as an animal model for negative symptoms of schizophrenia.     

The effect of clozapine on caudate nucleus volume in schizophrenic patients previously treated with typical antipsychotics.

Typical antipsychotics have been reported to enlarge the caudate nucleus in schizophrenic patients. The atypical antipsychotic, clozapine, is associated with a decrease in caudate size in patients previously treated with typical antipsychotics. The present study investigates whether a change in caudate volume after switching from treatment with typical antipsychotics to treatment with clozapine is related to improvement in symptoms or tardive dyskinesia (TD). Twenty-six schizophrenic patients participated in this open study. Caudate nucleus volume and TD were assessed before discontinuing typical antipsychotics and after 24 weeks of treatment with clozapine. After discontinuing typical antipsychotics, symptoms were assessed in a 3 days drug-free period and subsequently once a month. Treatment with clozapine resulted in a decrease in caudate volume, improvement in symptoms and amelioration of TD. However, no difference in caudate volume changes was found between responders and non-responders to clozapine and no correlations were found between caudate volume changes and reduction of TD. In conclusion, this study replicates earlier findings that clozapine decreases caudate volume in patients previously treated with typical antipsychotics and suggests that this effect is unrelated to treatment response or to amelioration of TD.     

Intramuscular preparations of antipsychotics: uses and relevance in clinical practice

Intramuscular formulations of antipsychotics can be sub-divided into two groups on the basis of their pharmacokinetic features: short-acting preparations and long-acting or depot preparations. Short-acting intramuscular formulations are used to manage acute psychotic episodes. On the other hand, long-acting compounds, also called "depot", are administered as antipsychotic maintenance treatment to ensure compliance and to eliminate bioavailability problems related to absorption and first pass metabolism. Adverse effects of antipsychotics have been studied with particular respect to oral versus short- and long-acting intramuscular formulations of the different compounds. For short-term intramuscular preparations the main risk with classical compounds are hypotension and extrapyramidal side effects (EPS). Data on the incidence of EPS with depot formulations are controversial: some studies point out that the incidence of EPS is significantly higher in patients receiving depot preparations, whereas others show no difference between oral and depot antipsychotics. Studies on the strategies for switching patients from oral to depot treatment suggest that this procedure is reasonably well tolerated, so that in clinical practice depot antipsychotic therapy is usually begun while the oral treatment is still being administered, with gradual tapering of the oral dose. Efficacy, pharmacodynamics and clinical pharmacokinetics of haloperidol decanoate, fluphenazine enanthate and decanoate, clopenthixol decanoate, zuclopenthixol decanoate and acutard, flupenthixol decanoate, perphenazine enanthate, pipothiazine palmitate and undecylenate, and fluspirilene are reviewed. In addition, the intramuscular preparations of atypical antipsychotics and clinical uses are reviewed. Olanzapine and ziprasidone are available only as short-acting preparations, while risperidone is to date the only novel antipsychotic available as depot formulation. To date, acutely ill, agitated psychotic patients have been treated with high parenteral doses of typical antipsychotics, which often cause serious EPS, especially dystonic reactions. Intramuscular formulations of novel antipsychotics (olanzapine and ziprasidone), which appear to have a better tolerability profile than typical compounds, showed an equivalent efficacy to parenteral typical agents in the acute treatment of psychoses. However, parenteral or depot formulations of atypical antipsychotics are not yet widely available.     

Retrospective database analysis on the effectiveness of typical and atypical antipsychotic drugs in an outpatient clinic setting

OBJECTIVE: To report the outcomes of a retrospective database analysis to compare the effectiveness of atypical and typical antipsychotic drugs. METHODS: Medical records of patients admitted to the psychiatry outpatient clinic between January 1998 and October 2005 were retrospectively reviewed. Data obtained from patient records were noted on a special form assessing four aspects of the treatment history: socio-demographic features, disease characteristics, initial treatment at the time of admission, and course of treatment. Patient groups (typical/atypical and Risperidone/Haloperidol/Olanzapine) were compared for time to all-cause medication discontinuation and rate of discontinuation. RESULTS: There was no statistically significant difference in the duration of treatment between patients using atypical (n = 150) and typical (n = 124) antipsychotics. The duration of treatment was significantly longer in patients on Haloperidol (n = 91) compared with those on Risperidone (n = 63). Rates of discontinuation over 18 months were 59.3% for patients on atypical antipsychotics and 57.3% for those on typical antipsychotics, and 68.3% for patients on Risperidone, 51.6% for patients on Haloperidol and 54.3% for patients on Olanzapine. CONCLUSION: Despite our hypothesis patients with chronic schizophrenia discontinued their atypical and typical antipsychotics, at a high rate with no significant difference indicating substantial limitations in the effectiveness of these drugs.     

Typical neuroleptics vs. atypical antipsychotics in the treatment of acute mania in a natural setting

The present retrospective chart review documents the treatment practice of in-patients suffering from acute manic or hypomanic episodes, at the Department of General Psychiatry, Medical University of Vienna between 1997 and 2001. The aim of the study was to compare the efficacy of typical neuroleptics and atypical antipsychotics as add-on therapy to mood stabilizers. A total of 119 episodes of consecutively admitted patients with ICD-10-defined acute mania (n=106) or hypomania (n=13) were included in a retrospective analysis. Two subgroups were separated out of the whole patient sample according to the medication used: (a) mood stabilizer+typical neuroleptic (n=27) and (b) mood stabilizer+atypical antipsychotic (n=39). The treatment patterns of both subgroups during the first 14 d of in-patient treatment were evaluated. The therapeutic effect was measured by the Clinical Global Impression Scale (CGI). Both patient groups showed no differences on CGI at admission. Patients treated with atypical antipsychotics showed a significantly greater clinical improvement after 14 d (p<0.005) and on discharge (p<0.05) than patients treated with typical neuroleptics. Furthermore, patients treated with atypical antipsychotics developed significantly less extrapyramidal side-effects (p<0.01) and were significantly treated less often with benzodiazepines (p<0.05) during the first 14 d compared to the group receiving typical neuroleptics. Based on our evaluation and the data available in the literature atypical antipsychotics can be considered as first choice for the treatment of acute mania as add-on therapy to mood stabilizers because of their better efficacy and side-effect profile compared to typical neuroleptics.     

Probabilistic classification and gambling in patients with schizophrenia receiving medication: comparison of risperidone, olanzapine, clozapine and typical antipsychotics

Rationale

We have previously shown that patients with schizophrenia treated with typical antipsychotics were impaired on the weather prediction probabilistic classification learning (PCL) task that relies on striatal function, and that similar patients treated with atypical antipsychotics were impaired on the Iowa gambling task (IGT) that depends on medial prefrontocortical function.

Objectives

We tested the hypothesis that test performance of patients treated with risperidone will be more similar to those treated with typical rather than atypical antipsychotics.

Results

Groups of schizophrenia patients treated with risperidone, olanzapine, clozapine or typical antipsychotics did not differ on the Positive and Negative Syndrome Scale or the Mini Mental State Exam (MMSE) but scored lower than controls on the MMSE. For the PCL task, patients treated with clozapine improved over trials while those treated with typical antipsychotics, olanzapine, or risperidone did not. For the IGT, patients treated with typical antipsychotics or risperidone improved over trials while those treated with clozapine or olanzapine did not.

Conclusions

Results generally supported the hypothesis that patients treated with risperidone perform more like those treated with typical antipsychotics than those treated with other atypical antipsychotics.     

Management of the negative symptoms of schizophrenia: new treatment options

This article presents a systematic review of pharmacological treatment for negative symptoms of schizophrenia, based on MEDLINE searches from 1995 to September 2002 to identify pertinent clinical trials. The pharmacotherapy of negative symptoms in schizophrenia includes novel/atypical antipsychotics and classical antipsychotics, as well as antidepressants, glutamatergic compounds, antiepileptic drugs and estrogens. In the assessment of therapy for negative symptoms of schizophrenia, it is imperative that better studies of sound methodology are performed. In such studies, some important aspects to be considered include an accurate definition and assessment of negative symptoms (including well designed, valid and reliable rating scales), the differentiation between primary and secondary negative symptoms, an appropriate selection of standard comparators, adequate dosages of comparators (e.g. haloperidol dosages) and an overall optimal study design. Most of the available studies on treating negative symptoms in schizophrenia have focused on the atypical antipsychotics, while other potential candidates, mostly in the context of add-on therapy, have not been so intensively investigated. Atypical antipsychotics have been proven in placebo-controlled trials to be effective in treating negative symptoms of acute schizophrenic episodes. In many of the comparator studies, they showed efficacy in treating negative symptoms that was superior to that of typical antipsychotics. Data on stable, predominant negative symptoms in subchronic or chronic cases of schizophrenia, although limited, have demonstrated the efficacy of atypical antipsychotics. If the beneficial tolerability profile with respect to extrapyramidal symptoms is also taken into account during clinical decision making, the atypical antipsychotics should be preferred for the treatment of negative symptoms. It is also worth noting that the traditional antipsychotics have the risk of inducing negative symptoms in the context of akinesia. The benefits of add-on therapy with SSRIs or a glutamatergic compound are well documented. Estrogen add-on therapy seems promising. Other traditionally suggested approaches, such as comedication with an antiepileptic drug, lithium or beta-adrenoceptor antagonist, cannot generally be recommended on the basis of the available data.