Evidence of Brain Dopamine Deficiency in Schizophrenia

1979 ◽  
Vol 24 (7) ◽  
pp. 661-667 ◽  
Author(s):  
Guy Chouinard ◽  
Barry D. Jones
Keyword(s):  
Negative Symptoms ◽  
Late Onset ◽  
Pharmacological Therapy ◽  
Positive Symptoms ◽  
Short Term ◽  
Onset Of Action ◽  
Double Blind ◽  
Dopamine Hypothesis ◽  
Term Basis ◽  
Dopamine Supersensitivity

Summary It is proposed that the increased dopamine function suggested by the dopamine hypothesis of schizophrenia is a dopaminergic postsynaptic receptor supersensitivity resulting from a dopamine deficiency. In support of this, three double-blind controlled studies conducted on drugs which alter brain dopaminergic activity in a manner different from that of classic neuroleptics are reported. 1) α-methyldopa-neuroleptic interaction proved efficacious for schizophrenic positive symptoms but only on a short-term basis. 2) Rubidium improved negative symptoms rapidly, and in contrast has a late onset of action on positive symptoms of schizophrenia. 3) Tryptophan-benserazide was efficacious in controlling both negative and positive symptoms of schizophrenia (although less so than chlorpromazine). It is concluded that currently accepted modes of pharmacological therapy (classical neuroleptics) are in the short-term controlling the dopamine supersensitivity secondary to a deficiency, but contributing in the long-term to increase the dopamine deficiency, and so exacerbate the supersensitivity. More effective forms of treatment may involve the use of agents which alter dopamine activity without inducing dopamine supersensitivity.

Efficacy of lurasidone across five symptom dimensions of schizophrenia: Pooled analysis of short-term, placebo-controlled studies

2015 ◽  
Vol 30 (1) ◽  
pp. 26-31 ◽  
Author(s):  
A. Loebel ◽  
J. Cucchiaro ◽  
R. Silva ◽  
Y. Mao ◽  
J. Xu ◽  
...  
Keyword(s):  
Effect Size ◽  
Repeated Measures ◽  
Negative Symptoms ◽  
Mixed Model ◽  
Five Factor Model ◽  
Pooled Analysis ◽  
Positive Symptoms ◽  
Factor Scores ◽  
Short Term ◽  
Double Blind

AbstractObjective:To evaluate the efficacy of lurasidone for schizophrenia using an established five-factor model of the Positive and Negative Syndrome Scale (PANSS).Methods:Patient-level data were pooled from five randomized, double-blind, placebo-controlled, 6-week studies of lurasidone (fixed doses, 40–160 mg/d) for patients with an acute exacerbation of schizophrenia. Changes in five established PANSS factors were assessed using mixed-model repeated measures analysis.Results:Compared with placebo (n = 496), lurasidone (n = 1029, dose groups pooled) significantly improved the PANSS total score at Week 6 (−22.6 vs. −12.8; P < 0.001; effect size, 0.45), as well as all factor scores (P < 0.001 for each): positive symptoms (−8.4 vs. −6.0; effect size, 0.43), negative symptoms (−5.2 vs. −3.3; effect size, 0.33), disorganized thought (−4.9 vs. −2.8; effect size, 0.42), hostility/excitement (−2.7 vs. −1.6; effect size, 0.31), and depression/anxiety (−3.2 vs. −2.3; effect size, 0.31). Separation from placebo occurred at Week 1 for the positive symptoms, disorganized thought, and hostility/excitement factors and at Week 2 for the other factors.Conclusions:In this pooled analysis of short-term studies in patients with acute schizophrenia, lurasidone demonstrated significant improvement for each of the five PANSS factor scores, indicating effectiveness across the spectrum of schizophrenia symptoms.

The Influence of Age and Sex on the Onset and Early Course of Schizophrenia

1993 ◽  
Vol 162 (1) ◽  
pp. 80-86 ◽  
Author(s):  
Heinz Häfner ◽  
Kurt Maurer ◽  
Walter Löffler ◽  
Anita Riecher-Rössler
Keyword(s):  
Negative Symptoms ◽  
Late Onset ◽  
Age At Onset ◽  
Age Distribution ◽  
Age Groups ◽  
Positive Symptoms ◽  
Early Course ◽  
Retrospective Assessment ◽  
Age And Sex ◽  
First Admission

A new standardised interview for the retrospective assessment of onset and early course of schizophrenia (IRAOS) was used to study the influence of age and sex on time of onset and psychopathology before first admission in 267 schizophrenic patients admitted for the first time. Mean age at onset, according to various operationalised definitions, differed by three to four years between the sexes. The age distribution at the earliest sign of mental disorder showed an early and steep increase until the age of 25 in males, and a delayed and smaller increase in females, with a second peak in women aged 45–79. Schizophrenia began with negative symptoms in 70% of cases, appearing two to six years before admission, and all positive symptoms appearing up to two years before. Both positive and negative symptoms accumulated exponentially. The early course of the disease was similar across age groups, except there was a longer period of negative symptoms before first admission in late-onset schizophrenia in women. The few significant age differences in symptoms were presumably due to general age-dependent reaction patterns like anxiety and depression or the cognitive development of personality, as indicated by an increase in fully elaborated positive symptoms, especially systematised paranoid delusions, with age.

Current use of atypical antipsychotics

2002 ◽  
Vol 17 (S4) ◽  
pp. 377s-384s ◽  
Author(s):  
F. Müller-Spahn
Keyword(s):  
Side Effects ◽  
Negative Symptoms ◽  
Atypical Antipsychotics ◽  
Term Treatment ◽  
Dopamine Neurons ◽  
Positive Symptoms ◽  
Onset Of Action ◽  
Conventional Antipsychotics ◽  
Long Term Treatment ◽  
Insufficient Response

SummaryIn terms of the phenomenology of schizophrenia, there are four targets for drug treatments: positive symptoms, negative symptoms, affective dysfunction, and cognitive dysfunction. Because of the side-effects of both conventional antipsychotics and the new atypicals, there still is a need to search for better-tolerated antipsychotics. Conventional antipsychotics have two principal limitations: 30–40% of patients have an insufficient response to them, and they have a large variety of adverse effects. Side-effects will reduce patients’ compliance with treatment, as well as their immediate quality of life, and may therefore unfavorably affect rehabilitation. Four principal features differentiate atypical from conventional antipsychotics, yet have not been established for all atypicals: fewer extrapyramidal side-effects, greater efficacy in the treatment of negative symptoms, specific pharmacological receptor binding profiles, and greater selective effect on the mesolimbic dopamine neurons than on nigrostriatal neurons. The pharmacological profile of amisulpride is completely different to that of other atypical antipsychotics. It has a high selectivity for D2 and D3 dopamine receptors, and thus would be expected to be devoid of unwanted side-effects associated with action on other neurotransmitter systems. It acts preferentially on the mesocortical and mesolimbic systems. It has an earlier onset of action than haloperidol. Amisulpride is a compound with a dual mode of action. At low doses it blocks presynaptic dopamine autoreceptors, inducing an increased dopaminergic neurotransmission, and at high doses it blocks postsynaptic dopaminergic activity. It is at least as effective as haloperidol, flupenthixol, and risperidone in controlling positive symptoms, as well as having efficacy for negative symptoms. It has less propensity to induce weight gain than do other atypical antipsychotics. For the 60–80% of patients with schizophrenia who require long-term treatment, drug tolerability is crucially important, as it will improve compliance, and therefore reduce relapse rate.

scholarly journals A Comparative Study between Olanzapine and Risperidone in the Management of Schizophrenia

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Saeed Shoja Shafti ◽  
Mahsa Gilanipoor
Keyword(s):  
Negative Symptoms ◽  
Primary Outcome ◽  
Positive Symptoms ◽  
Random Allocation ◽  
Severity Scale ◽  
Double Blind ◽  
Safety And Efficacy ◽  
Superior Efficacy ◽  
Schizophrenic Patients ◽  
Risperidone Group

Introduction. Since a variety of comparisons between risperidone and olanzapine have resulted in diverse outcomes, so safety and efficacy of them were compared again in a new trial.Method. Sixty female schizophrenic patients entered into one of the assigned groups for random allocation to olanzapine or risperidone (n=30in each group) in a double-blind, 12-week clinical trial. Scale for Assessment of Positive Symptoms (SAPS) and Scale for Assessment of Negative Symptoms (SANS) were used as the primary outcome measures. Clinical Global Impressions-Severity Scale (CGI-S), Schedule for Assessment of Insight (SAI), and finally Simpson Angus Scale (SAS) as well were employed as secondary scales.Results. While both of olanzapine and risperidone were significantly effective for improvement of positive symptoms (P<0.0001), as regards negative symptoms, it was so only by means of olanzapine (P<0.0003). CGI-S and SAI, as well, were significantly improved in both of the groups. SAS increment was significant only in the risperidone group (P<0.02).Conclusion. While both of olanzapine and risperidone were equally effective for improvement of positive symptoms and insight, olanzapine showed superior efficacy with respect to negative symptoms, along with lesser extrapyramidal side effects, in comparison with risperidone.

Efficacy and safety of MIN-101: A new drug for the treatment of negative symptoms in schizophrenia a 12-week randomized, double blind, placebo-controlled trial

2017 ◽  
Vol 41 (S1) ◽  
pp. S191-S191
Author(s):  
R. Luthringer
Keyword(s):  
Primary Endpoint ◽  
Negative Symptoms ◽  
Controlled Trial ◽  
Specific Treatment ◽  
Positive Symptoms ◽  
Double Blind ◽  
Five Factors ◽  
Symptom Scores ◽  
Clinically Significant ◽  
Metabolic Indices

ObjectiveTo compare the efficacy, safety, and tolerability of MIN-101, a compound with high affinities for sigma 2 and 5-HT 2A receptors, to placebo in treating negative symptoms, in stabilized patients with schizophrenia.MethodsThis multi-national phase 2b trial enrolled 244 patients with schizophrenia who were symptomatically stable for ≥ 3 months prior to entering the trial and had scores ≥ 20 negative subscale of the PANSS. Patients were randomized to monotherapy with MIN-101 32 mg/day, MIN-101 64 mg/day or placebo in a 1:1:1 ratio. The primary endpoint was the PANSS negative symptom score based on the five factors (pentagonal) model.ResultsStatistically significant reduction in the primary endpoint score was demonstrated for MIN-101 32 mg and 64 mg compared to placebo (P ≤ 0.022, ES 0.45 and ≤ 0.003, ES 0.58, respectively). This was supported by similar effects on most of the secondary measurements including: the PANSS three factors negative symptoms subscale, PANSS total score, CGI, BACS, CDSS, and PSP. There were no statistically significant differences in PANSS positive subscale scores between MIN-101 and placebo. No weight gain or clinically significant changes in vital sings, prolactin levels, routine laboratory values, metabolic indices and extrapyramidal symptom scores (EPS) were observed.ConclusionsSince positive symptoms and EPS did not change, the improvement in negative symptoms was not secondary to improvement in positive symptoms or EPS, suggesting that MIN-101 might be the first specific treatment to have a direct effect on negative symptoms.Disclosure of interestI have received consultant fees from Minerva Neuroscience the sponsor of this trial and own stock of Minerva Neuroscience

scholarly journals Comparison of therapeutic effects of monotherapy of chlorpromazine, risperidone and their combination in newly diagnosed schizophrenic patients

2018 ◽  
Vol 7 (7) ◽  
pp. 1273
Author(s):  
Tarun Vijaywargia
Keyword(s):  
Negative Symptoms ◽  
Positive Symptom ◽  
Therapeutic Effects ◽  
Positive Symptoms ◽  
Newly Diagnosed ◽  
Anti Psychotic ◽  
Double Blind ◽  
Oral Risperidone ◽  
Beneficial Effects ◽  
Schizophrenic Patients

Background: This study evaluates and compares how negative and positive symptoms of schizophrenia were influenced with monotherapy with a first-generation anti-psychotic medication (Chlorpromazine) and a second generation anti-psychotic medication (Risperidone) and by their combination, both of which are commonly used in clinical psychiatric practice.Methods: It was randomized, double-blind, controlled clinical study performed in Indian newly diagnosed schizophrenic patients in the Department of psychiatry from Feb 2003 to March 2004. Patients 18 (eighteen) patients aged 20 to 60 years diagnosed schizophrenics according to ICD-10 Criteria who visited in outpatient department of psychiatry during study period. Three groups of 6 Patient each, group-1 - was treated with oral Chlorpromazine 100 mg 12 hly, group -2 - was treated with oral Risperidone 2mg 12 hly group 3 -was treated with combination of oral Chlorpromazine 100mg 12 hly + oral Risperidone 2 mg 12 hly. How symptomatology in schizophrenic patients affected, is measured by applying various validated psychiatric scales like Brief psychiatric Rating Score (BPRS), Scale for assessment of positive symptom(SAPS), and Scale for Assessment of Negative Symptoms (SANS).Results: the study showed that the combination therapy of oral Chlorpromazine 100 mg 12 hly + Risperidone 2mg 12 hly had reduced the overall beneficial effects which were achieved with monotherapy of both the drugs.Conclusions: In this study, the therapeutic effects of combination of oral Chlorpromazine 100 mg 12 hly + Risperidone 2 mg 12 hly found to be reduced on positive symptoms and negative symptoms of schizophrenia, assessed on SAPS and SANS scoring scales when compared with beneficial effects which were achieved with monotherapy of both the drugs.

Treatment of Negative Symptoms in Schizophrenia with Amisulpride

1995 ◽  
Vol 166 (1) ◽  
pp. 68-72 ◽  
Author(s):  
P. Boyer ◽  
Y. Lecrubier ◽  
A. J. Puech ◽  
J. Dewailly ◽  
F. Aubin
Keyword(s):  
Negative Symptoms ◽  
Controlled Trial ◽  
Positive Symptoms ◽  
Receptor Blockade ◽  
Low Doses ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Dopaminergic Transmission ◽  
Parallel Group ◽  
Primary Evaluation

BackgroundThe efficacy of low doses of certain neuroleptics in improving negative symptoms is still controversial. This study assessed the efficacy of amisulpride, a benzamide which increases dopaminergic transmission at low doses via presynaptic dopamine receptor blockade, on negative symptoms of schizophrenia.MethodThe study was designed as a parallel-group, double-blind, placebo-controlled trial. Patients had to fulfil DSM–III criteria for schizophrenia, Andreasen's criteria for negative schizophrenia, and to have a total score of at least 75 on the SANS; those treated with neuroleptics or antidepressants underwent a six-week placebo wash-out. One hundred and four in-patients were randomly assigned to amisulpride 100 mg/d, amisulpride 300 mg/d, or placebo for six weeks; 85 patients completed the study.ResultsBoth amisulpride doses were significantly more effective than placebo on the primary evaluation criterion (SANS total score, MANOVAP< 0.02). No significant changes were found in positive symptoms or in extrapyramidal symptoms.ConclusionsNegative symptoms can be improved by low doses of amisulpride, favouring the hypothesis of dopaminergic hypofunction as one of the causes of negative symptoms.

L-DOPA in the Treatment of Negative Schizophrenic Symptoms: A Single-Subject Experimental Study

1986 ◽  
Vol 15 (3) ◽  
pp. 293-298 ◽  
Author(s):  
Stanley R. Kay ◽  
Lewis A. Opler
Keyword(s):  
Negative Symptoms ◽  
Psychomotor Retardation ◽  
Adjunctive Treatment ◽  
Single Subject ◽  
Abstract Thinking ◽  
Positive Symptoms ◽  
Drug Induced ◽  
Double Blind ◽  
Reversal Design ◽  
Negative Syndrome

Adjunctive Sinemet (L-DOPA plus carbidopa) therapy was assessed for a neuroleptic nonresponsive schizophrenic with a longstanding negative syndrome. A twenty-seven week double-blind placebo-controlled reversal design found significant improvement specifically for negative symptoms while treated with combined haloperidol-Sinemet as compared against haloperidol-placebo. The eight-week adjunctive treatment reversed a worsening trend in attention, abstract thinking, passive withdrawal, psychomotor retardation, and a cluster of seven negative parameters, while positive symptoms were unaffected. This seemed to represent more than simple reversal of drug-induced akinesia and underscores the importance of distinguishing between positive and negative syndromes in psychopharmacological research.

Quantitative Comparison of Clinical Effectiveness of Chlorpromazine and Promazine

1959 ◽  
Vol 105 (439) ◽  
pp. 508-510 ◽  
Author(s):  
Thomas H. Gilmore ◽  
Leo Shatin
Keyword(s):  
Clinical Effectiveness ◽  
Quantitative Comparison ◽  
Blind Study ◽  
Therapeutic Effectiveness ◽  
Double Blind Study ◽  
Short Term ◽  
Double Blind ◽  
Comparative Response ◽  
Term Basis

A double-blind study of chlorpromazine and promazine was conducted to measure their comparative therapeutic effectiveness on a short-term basis at medium dosage levels, such as might be used for out-patient purposes. The patients chosen, however, represented a more therapeutically challenging group of hospitalized acute schizophrenics in whom a dramatic and convincing effect might offer an evaluation of comparative response.

scholarly journals Effects of Brexpiprazole Across Symptom Domains in Patients With Schizophrenia: Post Hoc Analysis of Short- and Long-Term Studies

2021 ◽  
Author(s):  
Stephen R Marder ◽  
Stine R Meehan ◽  
Catherine Weiss ◽  
Dalei Chen ◽  
Mary Hobart ◽  
...  
Keyword(s):  
Negative Symptoms ◽  
Positive Symptoms ◽  
Confidence Limits ◽  
Double Blind ◽  
Post Hoc Analysis ◽  
Short And Long Term ◽  
Post Hoc ◽  
Anxiety Depression ◽  
Long Term Studies

Abstract The successful treatment of schizophrenia entails improvement across a spectrum of symptoms. The aim of this post hoc analysis was to characterize the short- and long-term effects of brexpiprazole on Positive and Negative Syndrome Scale (PANSS) ‘Marder factors’. Data were included from three 6-week, randomized, double-blind, placebo-controlled studies; a 52-week, randomized, double-blind, placebo-controlled maintenance treatment study; and two 52-week open-label extension (OLEx) studies – all in schizophrenia (DSM-IV-TR criteria). Patients receiving oral brexpiprazole were dosed at 2–4 mg/day (short-term studies) or 1–4 mg/day (long-term studies). At Week 6, least squares mean differences (LSMDs, with 95% confidence limits) for brexpiprazole (n=868) versus placebo (n=517) were: Positive symptoms: -1.55 (-2.30, -0.80), p&lt;0.0001, Cohen’s d effect size (ES)=0.27; Negative symptoms: -1.12 (-1.63, -0.61), p&lt;0.0001, ES=0.29; Disorganized thought: -1.26 (-1.78, -0.74), p&lt;0.0001, ES=0.32; Uncontrolled hostility/excitement: -0.76 (-1.15, -0.37), p=0.0002, ES=0.26; Anxiety/depression: -0.56 (-0.91, -0.22), p=0.0014, ES=0.22. At last visit of the maintenance study, LSMDs (95% confidence limits) for brexpiprazole (n=96) versus placebo (n=104) were: Positive symptoms: -3.44 (-4.99, -1.89), p&lt;0.0001, ES=0.62; Negative symptoms: -1.23 (-2.52, 0.07), p=0.063, ES=0.27; Disorganized thought: -1.69 (-2.81, -0.56), p=0.0035, ES=0.42; Uncontrolled hostility/excitement: -1.26 (-2.12, -0.39), p=0.0046, ES=0.41; Anxiety/depression: -0.72 (-1.47, 0.03), p=0.061, ES=0.27. In the OLEx studies, improvements were maintained over 58 (6 + 52) weeks of brexpiprazole treatment. In conclusion, these data suggest that brexpiprazole treats the continuum of schizophrenia symptoms, in the short- and long-term. Trial Registration: Data used in this post hoc analysis came from ClinicalTrials.gov identifiers: NCT01396421, NCT01393613, NCT01810380, NCT01668797, NCT01397786, NCT01810783.

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