The role of cannabidiol oil in schizophrenia treatment. a systematic review and meta-analysis.

The purpose of the present meta-analysis was to assess the efficacy of cannabidiol (CBD) oil in patients with schizophrenia. A search was conducted in EMBASE, PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) up to April 24th, 2020. Randomized clinical trials (RCTs), which used CBD oil treatment versus placebo or any other antipsychotic in schizophrenia patients either as monotherapy or add-on therapy, were included. Data were pooled using a random-effects model. The primary outcomes were efficacy as measured by total symptoms of schizophrenia and improvement in cognition. The meta-analysis was registered with PROSPERO [number: CRD42020157146]. Three double-blind RCTs were included. In one study, CBD oil was compared with amisulpride as monotherapy treatment, but no statistically significant difference in overall efficacy was detected between them. No data were available for cognition. The other two studies estimated the effects of CBD oil as add-on treatment compared to placebo; no significant difference was found either in overall efficacy or in cognition. Altogether, insufficient evidence exists on the efficacy and safety of CBD oil in schizophrenia patients. More RCTs, comparing CBD oil with placebo and other antipsychotics are warranted.

Amisulpride for very late-onset schizophrenia-like psychosis: the ATLAS three-arm RCT.

BACKGROUND: Very late-onset (aged ≥ 60 years) schizophrenia-like psychosis (VLOSLP) occurs frequently but no placebo-controlled, randomised trials have assessed the efficacy or risks of antipsychotic treatment. Most patients are not prescribed treatment. OBJECTIVES: The study investigated whether or not low-dose amisulpride is superior to placebo in reducing psychosis symptoms over 12 weeks and if any benefit is maintained by continuing treatment thereafter. Treatment safety and cost-effectiveness were also investigated. DESIGN: Three-arm, parallel-group, placebo-controlled, double-blind, randomised controlled trial. Participants who received at least one dose of study treatment were included in the intention-to-treat analyses. SETTING: Secondary care specialist old age psychiatry services in 25 NHS mental health trusts in England and Scotland. PARTICIPANTS: Patients meeting diagnostic criteria for VLOSLP and scoring > 30 points on the Brief Psychiatric Rating Scale (BPRS). INTERVENTION: Participants were randomly assigned to three arms in a two-stage trial: (1) 100 mg of amisulpride in both stages, (2) amisulpride then placebo and (3) placebo then amisulpride. Treatment duration was 12 weeks in stage 1 and 24 weeks (later reduced to 12) in stage 2. Participants, investigators and outcome assessors were blind to treatment allocation. MAIN OUTCOME MEASURES: Primary outcomes were psychosis symptoms assessed by the BPRS and trial treatment discontinuation for non-efficacy. Secondary outcomes were extrapyramidal symptoms measured with the Simpson-Angus Scale, quality of life measured with the World Health Organization's quality-of-life scale, and cost-effectiveness measured with NHS, social care and carer work loss costs and EuroQol-5 Dimensions. RESULTS: A total of 101 participants were randomised. Ninety-two (91%) participants took the trial medication, 59 (64%) completed stage 1 and 33 (56%) completed stage 2 treatment. Despite suboptimal compliance, improvements in BPRS scores at 12 weeks were 7.7 points (95% CI 3.8 to 11.5 points) greater with amisulpride than with placebo (11.9 vs. 4.2 points; p = 0.0002). In stage 2, BPRS scores improved by 1.1 point in those who continued with amisulpride but deteriorated by 5.2 points in those who switched from amisulpride to placebo, a difference of 6.3 points (95% CI 0.9 to 11.7 points; p = 0.024). Fewer participants allocated to the amisulpride group stopped treatment because of non-efficacy in stages 1 (p = 0.01) and 2 (p = 0.031). The number of patients stopping because of extrapyramidal symptoms and other side effects did not differ significantly between groups. Amisulpride treatment in the base-case analyses was associated with non-significant reductions in combined NHS, social care and unpaid carer costs and non-significant reductions in quality-adjusted life-years (QALYs) in both stages. Including patients who were intensive users of inpatient services in sensitivity analyses did not change the QALY result but resulted in placebo dominance in stage 1 and significant reductions in NHS/social care (95% CI -£8923 to -£122) and societal costs (95% CI -£8985 to -£153) for those continuing with amisulpride. LIMITATIONS: The original recruitment target of 300 participants was not achieved and compliance with trial medication was highly variable. CONCLUSIONS: Low-dose amisulpride is effective and well tolerated as a treatment for VLOSLP, with benefits maintained by prolonging treatment. Potential adverse events include clinically significant extrapyramidal symptoms and falls. FUTURE WORK: Trials should examine the longer-term effectiveness and safety of antipsychotic treatment in this patient group, and assess interventions to improve their appreciation of potential benefits of antipsychotic treatment and compliance with prescribed medication. TRIAL REGISTRATION: Current Controlled Trials ISRCTN45593573 and EudraCT2010-022184-35. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 67. See the NIHR Journals Library website for further project information.

Amisulpride-CD-Loaded Liposomes: Optimization and In Vivo Evaluation.

Amisulpride (AMS) is an atypical antipsychotic agent used for the treatment of schizophrenia. The effect of different variables, i.e., the type of cyclodextrins (CDs), ratio of drug/CDs, and type of loading on the prepared AMS-CD liposomes (single and double loaded) was studied by applying 23 full factorial design. Double-loaded liposomes are loaded with AMS-hydroxyl propyl-ß-cyclodextrin (HP-ß-CD) in the aqueous phase and free drug in the lipophilic bilayer, while single-loaded liposomes are loaded only with AMS-HP-ß-CD in the aqueous phase. Entrapment efficiency, particle size, polydespersibility, and zeta potential were selected as dependent variables. Design Expert® software was used to obtain an optimized formulation with high entrapment efficiency (64.55 ± 1.27%), average particle size of 40.1 ± 2.77 nm, polydespersibility of 0.44 ± 0.37, and zeta potential of - 48.8 ± 0.28. Optimized formula was evaluated for in vitro release, surface morphology and stability study was also conducted. AMS-HP-ß-CD in double-loaded liposomes exhibited higher drug release than those in the conventional liposomes and in the single-loaded liposomes. The maximum plasma concentration (Cmax) of AMS in optimized AMS-HP-ß-CD double-loaded liposomal formulation increased by 1.55- and 1.29-fold, as compared to the commercial tablets and conventional liposomes, respectively. However, the relative bioavailability of AMS double-loaded liposomes was 1.94- and 1.28-folds of commercial tablet and conventional liposomes, respectively.

Sulpiride, Amisulpride, Thioridazine, and Olanzapine: Interaction with Model Membranes. Thermodynamic and Structural Aspects.

Neuroleptic drugs are widely applied in effective treatment of schizophrenia and related disorders. The lipophilic character of neuroleptics means that they tend to accumulate in the lipid membranes, impacting their functioning and processing. In this paper, the effect of four drugs, namely, thioridazine, olanzapine, sulpiride, and amisulpride, on neutral and negatively charged lipid bilayers was examined. The interaction of neuroleptics with lipids and the subsequent changes in the membrane physical properties was assessed using several complementary biophysical approaches (isothermal titration calorimetry, electron paramagnetic resonance spectroscopy, dynamic light scattering, and ζ potential measurements). We have determined the thermodynamic parameters, that is, the enthalpy of interaction and the binding constant, to describe the interactions of the investigated drugs with model membranes. Unlike thioridazine and olanzapine, which bind to both neutral and negatively charged membranes, amisulpride interacts with only the negatively charged one, while sulpiride does not bind to any of them. The mechanism of olanzapine and thioridazine insertion into the bilayer membrane cannot be described merely by a simple molecule partition between two different phases (the aqueous and the lipid phase). We have estimated the number of protons transferred in the course of drug binding to determine which of its forms, ionized or neutral, binds more strongly to the membrane. Finally, electron paramagnetic resonance results indicated that the drugs are localized near the water-membrane interface of the bilayer and presence of a negative charge promotes their burying deeper into the membrane.

Augmentation with amisulpride for schizophrenic patients non-responsive to risperidone monotherapy.

INTRODUCTION: The combination of antipsychotic drugs is a therapeutic resource in clinical practice. This study aimed to evaluate the efficacy and security of adding amisulpride in patients who at least partially responded to risperidone. METHODS: A 3-month, open, observational study was undertaken to evaluate the effectiveness of adding amisulpride in subjects who scored at least 25 on the brief psychiatric rating scale (BPRS) after risperidone monotherapy. Patients were evaluated with BPRS, the Clinical Global Impressions Severity of Illness scale (CGI-S) and the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (UKU) at baseline, 1 and 3 months. RESULTS: Coadjuvant treatment with amisulpride achieves a statistically significant improvement in mental status over a period of 3 months when measured with BPRS, CGI and UKU scales. The response rate was 70 (45%) in the oral risperidone and 74 (28%) in the parenteral risperidone groups. DISCUSSION: The addition of amisulpride could lead to an improvement in schizophrenia symptoms in patients that do not, or only partially, respond to risperidone. Further research is required into alternative therapies for poor responders.

Cannabis and schizophrenia.

BACKGROUND: Schizophrenia is a mental illness causing disordered beliefs, ideas and sensations. Many people with schizophrenia smoke cannabis, and it is unclear why a large proportion do so and if the effects are harmful or beneficial. It is also unclear what the best method is to allow people with schizophrenia to alter their cannabis intake. OBJECTIVES: To assess the effects of specific psychological treatments for cannabis reduction in people with schizophrenia.To assess the effects of antipsychotics for cannabis reduction in people with schizophrenia.To assess the effects of cannabinoids (cannabis related chemical compounds derived from cannabis or manufactured) for symptom reduction in people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register, 12 August 2013, which is based on regular searches of BIOSIS, CINAHL, EMBASE, MEDLINE, PUBMED and PsycINFO.We searched all references of articles selected for inclusion for further relevant trials. We contacted the first author of included studies for unpublished trials or data. SELECTION CRITERIA: We included all randomised controlled trials involving cannabinoids and schizophrenia/schizophrenia-like illnesses, which assessed:1) treatments to reduce cannabis use in people with schizophrenia;2) the effects of cannabinoids on people with schizophrenia. DATA COLLECTION AND ANALYSIS: We independently inspected citations, selected papers and then re-inspected the studies if there were discrepancies, and extracted data. For dichotomous data we calculated risk ratios (RR) and for continuous data, we calculated mean differences (MD), both with 95% confidence intervals (CI) on an intention-to-treat basis, based on a fixed-effect model. We excluded data if loss to follow-up was greater than 50%. We assessed risk of bias for included studies and used GRADE to rate the quality of the evidence. MAIN RESULTS: We identified eight randomised trials, involving 530 participants, which met our selection criteria.For the cannabis reduction studies no one treatment showed superiority for reduction in cannabis use. Overall, data were poorly reported for many outcomes of interest. Our main outcomes of interest were medium-term data for cannabis use, global state, mental state, global functioning, adverse events, leaving the study early and satisfaction with treatment. 1. Reduction in cannabis use: adjunct psychological therapies (specifically about cannabis and psychosis) versus treatment as usualResults from one small study showed people receiving adjunct psychological therapies specifically about cannabis and psychosis were no more likely to reduce their intake than those receiving treatment as usual (n = 54, 1 RCT, MD -0.10, 95% CI -2.44 to 2.24, moderate quality evidence). Results for other main outcomes at medium term were also equivocal. No difference in mental state measured on the PANSS positive were observed between groups (n = 62, 1 RCT, MD -0.30 95% CI -2.55 to 1.95, moderate quality evidence). Nor for the outcome of general functioning measured using the World Health Organization Quality of Life BREF (n = 49, 1 RCT, MD 0.90 95% CI -1.15 to 2.95, moderate quality evidence). No data were reported for the other main outcomes of interest 2. Reduction in cannabis use: adjunct psychological therapy (specifically about cannabis and psychosis) versus adjunct non-specific psychoeducation One study compared specific psychological therapy aimed at cannabis reduction with general psychological therapy. At three-month follow-up, the use of cannabis in the previous four weeks was similar between treatment groups (n = 47, 1 RCT, RR 1.04 95% CI 0.62 to 1.74, moderate quality evidence). Again, at a medium-term follow-up, the average mental state scores from the Brief Pscychiatric Rating Scale-Expanded were similar between groups (n = 47, 1 RCT, MD 3.60 95% CI - 5.61 to 12.81, moderate quality evidence). No data were reported for the other main outcomes of interest: global state, general functioning, adverse events, leaving the study early and satisfaction with treatment. 3. Reduction in cannabis use: antipsychotic versus antipsychotic In a small trial comparing effectiveness of olanzapine versus risperidone for cannabis reduction, there was no difference between groups at medium-term follow-up (n = 16, 1 RCT, RR 1.80 95% CI 0.52 to 6.22, moderate quality evidence). The number of participants leaving the study early at medium term was also similar (n = 28, 1 RCT, RR 0.50 95% CI 0.19 to 1.29, moderate quality evidence). Mental state data were reported, however they were reported within the short term and no difference was observed. No data were reported for global state, general functioning, and satisfaction with treatment.With regards to adverse effects data, no study reported medium-term data. Short-term data were presented but overall, no real differences between treatment groups were observed for adverse effects. 4. Cannabinoid as treatment: cannabidiol versus amisulprideAgain, no data were reported for any of the main outcomes of interest at medium term. There were short-term data reported for mental state using the BPRS and PANSS, no overall differences in mental state were observed between treatment groups. AUTHORS' CONCLUSIONS: Results are limited and inconclusive due to the small number and size of randomised controlled trials available and quality of data reporting within these trials. More research is needed to a) explore the effects of adjunct psychological therapy that is specifically about cannabis and psychosis as currently there is no evidence for any novel intervention being better than standard treatment,for those that use cannabis and have schizophrenia b) decide the most effective drug treatment in treating those that use cannabis and have schizophrenia, and c) assess the effectiveness of cannabidiol in treating schizophrenia. Currently evidence is insufficient to show cannabidiol has an antipsychotic effect.

Effects of dopamine D2/D3 blockade on human sensory and sensorimotor gating in initially antipsychotic-naive, first-episode schizophrenia patients.

It has been suggested that psychophysiological measures of sensory and sensorimotor gating, P50 gating and prepulse inhibition of the startle reflex (PPI), underlie core features of schizophrenia and are linked to dopaminergic pathways in the striatum and prefrontal cortex. In the present study, the effects of a potent D2/D3 receptor antagonist, amisulpride, were investigated on PPI and P50 gating in a large sample of antipsychotic-naive, first-episode patients with schizophrenia. A total of 52 initially antipsychotic-naive, first-episode schizophrenia patients were assessed for their P50 gating, PPI, and habituation/sensitization abilities at baseline and after 2 and 6 weeks of treatment with flexible doses of amisulpride. In addition, 47 matched healthy controls were assessed at baseline and after 6 weeks. At baseline, the patients showed significantly reduced PPI, yet normal levels of P50 gating, habituation, and sensitization. Treatment with amisulpride showed no effects on these measures, either at 2 or 6 weeks of follow-up. This is the first study investigating the effects of monotherapy with a relatively selective dopamine D2/D3 receptor antagonist (amisulpride) on sensory and sensorimotor gating deficits in a longitudinal study of a large group of initially antipsychotic-naive, first-episode patients with schizophrenia. Our finding that amisulpride effectively reduced symptom severity in our patients without reducing their PPI deficits indicates that increased activity of dopamine D2 receptors may be involved in symptomatology of patients with schizophrenia, but not in their sensorimotor gating deficits.

Influence of aripiprazole, risperidone, and amisulpride on sensory and sensorimotor gating in healthy 'low and high gating' humans and relation to psychometry.

Despite advances in the treatment of schizophrenia spectrum disorders with atypical antipsychotics (AAPs), there is still need for compounds with improved efficacy/side-effect ratios. Evidence from challenge studies suggests that the assessment of gating functions in humans and rodents with naturally low-gating levels might be a useful model to screen for novel compounds with antipsychotic properties. To further evaluate and extend this translational approach, three AAPs were examined. Compounds without antipsychotic properties served as negative control treatments. In a placebo-controlled, within-subject design, healthy males received either single doses of aripiprazole and risperidone (n=28), amisulpride and lorazepam (n=30), or modafinil and valproate (n=30), and placebo. Prepulse inhibiton (PPI) and P50 suppression were assessed. Clinically associated symptoms were evaluated using the SCL-90-R. Aripiprazole, risperidone, and amisulpride increased P50 suppression in low P50 gaters. Lorazepam, modafinil, and valproate did not influence P50 suppression in low gaters. Furthermore, low P50 gaters scored significantly higher on the SCL-90-R than high P50 gaters. Aripiprazole increased PPI in low PPI gaters, whereas modafinil and lorazepam attenuated PPI in both groups. Risperidone, amisulpride, and valproate did not influence PPI. P50 suppression in low gaters appears to be an antipsychotic-sensitive neurophysiologic marker. This conclusion is supported by the association of low P50 suppression and higher clinically associated scores. Furthermore, PPI might be sensitive for atypical mechanisms of antipsychotic medication. The translational model investigating differential effects of AAPs on gating in healthy subjects with naturally low gating can be beneficial for phase II/III development plans by providing additional information for critical decision making.

Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.

Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.

Treatment with amisulpride of addicted patients to psychoactive substances and psychotic symptoms.

INTRODUCTION: There is ever more available information on the effectiveness of second-generation antipsychotic drugs used in addictive behaviour patients with psychotic symptoms. Due to its characteristics, Amisulpride is a medicine that can be considered as a valid therapeutic option to treat this group of patients. OBJECTIVE: To assess the value of Amisulpride to treat patients with addictive behaviours, and the associated morbidity. METHOD: An experimental, prospective study was conducted. A total of 97 ambulatory patients, who were initiating, or already receiving, treatment at the Addictive Behaviours Unit in Paterna, Valencia (Spain), were selected to take part in the study. Inclusion criteria included female and male patients, diagnosed of missusing any of the following substances: alcohol, heroine, cocaine or cannabis, who having overcome the detoxification phase, presented one or more of the following symptoms: paranoid ideas, hostility, severe irritative or impulsive behaviours, interpersonal sensitivity, and hearing or visual allucinations. An initial dose of Amisulpride, standardized in two ranges (100-300 mg y >/= 400 mg) was used. It was progressively increased according to the clinical response. Four assessments were conducted at months 0, 3, 6 and 9. RESULTS: Out of a total of 97 patients, 14 were excluded due to violation of the protocol. Twenty patients dropped out and 63 completed the follow-up period. Mean Amilsupride daily dose was 493.5 ± 197.1 mg In those patients who completed the treatment, an overall improvement in their psychological distress, a decreased in craving and an improvement in their psychological and social functioning were found. CONCLUSION: Treatment with Amisulpride seems to be effective in patients who are on different addictive substances, and its associated morbidity, both at a short and a medium period of time.

Enantioselective analysis of amisulpride in pharmaceutical formulations by means of capillary electrophoresis.

A capillary electrophoretic method has been developed for the enantioselective analysis of amisulpride in pharmaceutical formulations, using beta-cyclodextrin sulfate as the chiral selector. Several parameters, such as cyclodextrin type and concentration, buffer concentration and pH and capillary temperature were investigated for method optimisation. Baseline enantioseparation of the racemic compound was achieved in less than 10 min using a fused silica capillary (50 microm i.d. and 33.0, 8.5 cm, total and effective length, respectively), filled with a background electrolyte consisting of a 10mM citrate buffer at pH 3.5 supplemented with 0.22% (w/v) beta-cyclodextrin sulfate at 20 degrees C and applying a voltage of +15 kV. Formulation analysis was carried out after analyte extraction by methanol. The method was fully validated, with good results in terms of precision, selectivity, accuracy and amount of drug found with respect to the label claim. Thus, the method seems to be suitable for the enantiomeric analysis of amisulpride in pharmaceutical formulations.

Sensorimotor gating and habituation of the startle response in schizophrenic patients randomly treated with amisulpride or olanzapine.

BACKGROUND: Schizophrenic patients exhibit impairments in prepulse inhibition (PPI) and habituation of the acoustic startle response (ASR). Recent studies suggested that PPI deficits and habituation deficits are normalized after antipsychotic treatment. Despite clear evidence of gating and habituation mechanisms in animal models, it is still unknown which neurotransmitter systems are involved in schizophrenic patients. Thus, we compared the effects of a combined 5-HT2A/D2 and a pure D2/D3 antagonist on PPI and habituation of ASR in patients with schizophrenia. METHODS: The ASR was measured in 37 acute schizophrenic patients who were randomized and double-blinded as to treatment with amisulpride or olanzapine. Patients were assessed during the first week and after four and eight weeks of treatment. Twenty healthy matched control subjects were examined likewise. RESULTS: Schizophrenic patients showed a significant PPI deficit and significantly decreased startle amplitude at baseline. The gating deficit disappeared after antipsychotic treatment in both treatment groups. Amisulpride sensitized the startle amplitude, whereas startle amplitude was not changed by olanzapine. After correcting for startle amplitude, patients did not show a habituation deficit; however, amisulpride accelerated habituation, whereas olanzapine had no effect. CONCLUSIONS: Our findings suggest that the PPI-restoring effect of antipsychotics is probably attributed to a dopamine D2 receptor blockade.

D2 receptor occupancy during high- and low-dose therapy with the atypical antipsychotic amisulpride: a 123I-iodobenzamide SPECT study.

UNLABELLED: Amisulpride appears to be an effective agent for treating positive or negative symptoms of schizophrenia, depending on dose. The aim of this study was to assess striatal dopamine D(2) receptor availability by means of (123)I-iodobenzamide (IBZM) SPECT in patients treated with high and low doses of this atypical antipsychotic drug. METHODS: Twenty-nine patients (19 men and 10 women, age range, 19-68 y) with schizophrenia treated with high doses (15 patients; 400-1,200 mg/d; mean dose, 666.7 +/- 219.3 mg/d) or low doses (14 patients; 50-300 mg/d; mean dose, 228.6 +/- 93.5 mg/d) of amisulpride were examined. For assessment of plasma amisulpride concentration, blood samples were taken. Brain SPECT was performed 2 h after intravenous injection of 185 MBq of (123)I-IBZM. For semiquantitative evaluation, transverse slices corrected for attenuation (Chang's first-order method) were used to calculate specific binding in the striatum, with the frontal cortex used as background. RESULTS: In all patients treated with amisulpride, specific binding of (123)I-IBZM to D(2) receptors was significantly lower (P < 0.001) than in healthy controls (0.95). Both groups treated with amisulpride differed significantly in specific binding of (123)I-IBZM to dopamine D(2) receptors (0.20 vs. 0.31, P < 0.05). D(2) receptor blockade correlated well with the administered dose of amisulpride and with amisulpride plasma concentration. CONCLUSION: Our findings suggest that amisulpride treatment leads to a significant occupancy of postsynaptic dopamine D(2) receptors. The blockade of D(2) receptors tends to be significantly lower in patients receiving low-dose amisulpride therapy than in patients receiving high-dose therapy.

Effects of amisulpride, risperidone and chlorpromazine on auditory and visual latent inhibition, prepulse inhibition, executive function and eye movements in healthy volunteers.

In view of the evidence that cognitive deficits in schizophrenia are critically important for long-term outcome, it is essential to establish the effects that the various antipsychotic compounds have on cognition, particularly second-generation drugs. This parallel group, placebo-controlled study aimed to compare the effects in healthy volunteers (n = 128) of acute doses of the atypical antipsychotics amisulpride (300 mg) and risperidone (3 mg) to those of chlorpromazine (100 mg) on tests thought relevant to the schizophrenic process: auditory and visual latent inhibition, prepulse inhibition of the acoustic startle response, executive function and eye movements. The drugs tested were not found to affect auditory latent inhibition, prepulse inhibition or executive functioning as measured by the Cambridge Neuropsychological Test Battery and the FAS test of verbal fluency. However, risperidone disrupted and amisulpride showed a trend to disrupt visual latent inhibition. Although amisulpride did not affect eye movements, both risperidone and chlorpromazine decreased peak saccadic velocity and increased antisaccade error rates, which, in the risperidone group, correlated with drug-induced akathisia. It was concluded that single doses of these drugs appear to have little effect on cognition, but may affect eye movement parameters in accordance with the amount of sedation and akathisia they produce. The effect risperidone had on latent inhibition is likely to relate to its serotonergic properties. Furthermore, as the trend for disrupted visual latent inhibition following amisulpride was similar in nature to that which would be expected with amphetamine, it was concluded that its behaviour in this model is consistent with its preferential presynaptic dopamine antagonistic activity in low dose and its efficacy in the negative symptoms of schizophrenia.

Is regionally selective D2/D3 dopamine occupancy sufficient for atypical antipsychotic effect? an in vivo quantitative [123I]epidepride SPET study of amisulpride-treated patients.

OBJECTIVE: Atypical antipsychotic drug treatment is clinically effective with a low risk of extrapyramidal symptoms. Explanations for the mechanism underlying this beneficial therapeutic profile of atypical over typical antipsychotic agents include 1) simultaneous antagonism of dopamine D(2) and serotonin 5-HT(2A) receptors or 2) selective action at limbic cortical dopamine D(2)-like receptors with modest striatal D(2) receptor occupancy. Amisulpride is an atypical antipsychotic drug with selective affinity for D(2)/D(3) dopamine receptors and provides a useful pharmacological model for examining these hypotheses. The authors' goal was to evaluate whether treatment with amisulpride results in "limbic selective" D(2)/D(3) receptor blockade in vivo. METHOD: Five hours of dynamic single photon emission tomography data were acquired after injection of [(123)I]epidepride (approximately 150 MBq). Kinetic modeling was performed by using the simplified reference region model to obtain binding potential values. Estimates of receptor occupancy were made relative to a healthy volunteer comparison group (N=6). RESULTS: Eight amisulpride-treated patients (mean dose=406 mg/day) showed moderate levels of D(2)/D(3) receptor occupancy in the striatum (56%), and significantly higher levels were seen in the thalamus (78%) and temporal cortex (82%). CONCLUSIONS: Treatment with amisulpride results in a similar pattern of limbic cortical over striatal D(2)/D(3) receptor blockade to that of other atypical antipsychotic drugs. This finding suggests that modest striatal D(2) receptor occupancy and preferential occupancy of limbic cortical dopamine D(2)/D(3) receptors may be sufficient to explain the therapeutic efficacy and low extrapyramidal symptom profile of atypical antipsychotic drugs, without the need for 5-HT(2A) receptor antagonism.

In vivo extrastriatal and striatal D2 dopamine receptor blockade by amisulpride in schizophrenia.

Amisulpride, a substituted benzamide with high affinity for dopamine D2 and D3 receptors only, has been reported to have therapeutic effects on both negative and positive schizophrenic symptoms, although at distinct dose ranges (50-300 mg/day vs. 400-1,200 mg/day). The purpose of this study was to investigate the binding of amisulpride to extrastriatal (i.e., thalamus and temporal cortex) and striatal D2 dopamine receptors with respect to plasma amisulpride determinations. Ten patients with schizophrenia treated with amisulpride over a wide range of doses (25-1,200 mg/day) were studied. Positron emission tomography images were acquired by using 76Br-FLB-457, a highly specific antagonist of the D2 and D3 dopamine receptors. Binding indexes (BI) in the regions studied were estimated with reference to values from six healthy subjects. A curvilinear relationship was demonstrated between plasma concentration of amisulpride and the BI in extrastriatal regions. The BI also varied as a function of plasma concentration in striatum. Furthermore, the data provide evidence for different binding profiles: low plasma concentrations (28-92 ng/mL) induced marked extrastriatal binding and low striatal binding, whereas higher plasma concentrations (>153 ng/mL) induced marked binding both in extrastriatal and striatal regions. Dose-dependent differential binding profiles of amisulpride to D2 receptors in extrastriatal and striatal regions were demonstrated, and two therapeutic ranges of plasma concentrations for negative and positive schizophrenic symptoms, respectively, are suggested.