Rosenheck, R. et al. Impact of clozapine on negative symptoms and on the deficit syndrome in refractory schizophrenia. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. Am. J. Psychiatry 156, 88-93
This study compared the effect of clozapine and haloperidol on positive and negative symptoms of schizophrenia and in patients with high levels of negative symptoms or the deficit syndrome.
Patients were participants in a 15-site double-blind, random-assignment Veterans Administration trial comparing clozapine (N=205) and haloperidol (N=217) in hospitalized patients with refractory schizophrenia. Analysis of covariance examining change at 6 weeks, 3 months, and 1 year evaluated 1) clozapine's effect on positive and negative syndromes; 2) clozapine's effect on each syndrome, statistically controlling for the other; and 3) the interaction of clozapine treatment and the presence or absence of high levels of negative symptoms at baseline and the deficit syndrome.
Patients treated with clozapine showed significantly greater improvement than control subjects on positive symptoms at all time points and on negative symptoms at 3 months. Clozapine had no independent effect on negative symptoms at any time after control for positive symptoms, but its effects on positive symptoms persisted after control for negative symptoms at 6 weeks only. There were no significant differences in response to clozapine between patients with high and low levels of negative symptoms at baseline or between patients with and without the deficit syndrome.
The greater effectiveness of clozapine as compared to conventional medications in refractory schizophrenia is not specific to either negative clinical symptoms or clinical subtypes defined by prominent negative symptoms or evidence of the deficit syndrome.
"That said, there may be patients with other types of confounding factors, as schizophrenia is known to be a heterogeneous disease (Tandon et al., 2009; Insel, 2010; Kanahara et al., 2013). Clozapine is known to improve symptoms in deficit syndrome (Rosenheck et al., 1999; Kelly et al., 2010). It is highly possible that in these patients, the mechanistic action is not via blockade of DRD2, but by modulation of other sites, such as the N-methyl- D-aspartate receptor, a candidate target of clozapine in the treatment of schizophrenia (Hashimoto, 2011; Miyamoto et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: Objective
Dopamine supersensitivity psychosis (DSP) is considered to be one cause of treatment-resistant schizophrenia (TRS). The authors investigated the efficacy of risperidone long-acting injections (RLAI) in patients with TRS and DSP.
This is a multicenter, prospective, 12-month follow-up, observational study that included unstable and severe TRS patients with and without DSP. 115 patients with TRS were recruited and divided into two groups according to the presence or absence of DSP which was judged on the basis of the clinical courses and neurological examinations. RLAI was administered adjunctively once every 2 weeks along with oral antipsychotics. We observed changes in scores for the Brief Psychiatric Rating Scales (BPRS), Clinical Global Impression—Severity of Illness (CGI-S), Global Assessment of Functioning Scale (GAF), and Extrapyramidal Symptom Rating Scale (ESRS) during the study. Of the assessed 94 patients, 61 and 33 were categorized into the DSP and NonDSP groups, respectively.
While baseline BPRS total scores, CGI-S scores and GAF scores did not differ, the ESRS score was significantly higher in the DSP group compared with the NonDSP group. Treatment significantly reduced BPRS total scores and CGI-S scores, and increased GAF scores in both groups, but the magnitudes of change were significantly greater in the DSP group relative to the NonDSP group. ESRS scores were also reduced in the DSP group. Responder rates (≥ 20% reduction in BPRS total score) were 62.3% in the DSP group and 21.2% in the NonDSP group.
It is suggested that DSP contributes to the etiology of TRS. Atypical antipsychotic drugs in long-acting forms, such as RLAI, can provide beneficial effects for patients with DSP.
Clinical trials registration: UMIN (UMIN000008487).
Schizophrenia Research 05/2014; 155(1-3). DOI:10.1016/j.schres.2014.02.022 · 3.92 Impact Factor
"The most consistent results regarding efficacy in this group of patients have been observed with clozapine. The data from open and controlled studies show superior effects of clozapine on positive and negative symptoms, compared to prior treatment with typical neuroleptics.[1317–20] It has been found that up to 60% of neuroleptic resistant patients treated with clozapine respond to it, half of these respond within 6 weeks of treatment, while the other half respond within 6months of treatment. "
[Show abstract][Hide abstract] ABSTRACT: This article summarizes the current knowledge base on the diagnosis and management of treatment resistant schizophrenia. While the prevalence of treatment resistant schizophrenia is definition dependent, estimates have ranged from 30% to up to 60%. This article first looks into the various diagnostic criteria of treatment resistant schizophrenia. Then the literature is reviewed about the pharmacotherapeutics of its management. Clozapine emerges to be the gold standard. In addition risperidone and high dose olanzapine also emerge as clinically useful options. Other emerging adjunctive treatment options are equally addressed.
Indian Journal of Psychiatry 03/2009; 51(4):254-60. DOI:10.4103/0019-5545.58289
"Schizophrenia is a disease with non-pathognomic symptoms, characterized by a multitude of facets, most notably psychosis, negative symptoms and cognitive deficits. Currently available antipsychotics alleviate the positive symptoms of psychosis and, to a more limited extent, also improve the negative signs (Tandon et al., 1993; Breier et al., 1994; Buchanan et al., 1998; Rosenheck et al., 1999). This limited spectrum of efficacy is, in turn, thought to hamper proper societal functioning of patients and their re-insertion into society (Freedman, 2003; Green et al., 2004). "
[Show abstract][Hide abstract] ABSTRACT: F15063 is a high affinity D(2)/D(3) antagonist, D(4) partial agonist, and high efficacy 5-HT(1A) agonist, with little affinity (40-fold lower than for D(2) receptors) at other central targets. Here, the profile of F15063 was evaluated in models of positive symptoms of schizophrenia and motor side-effects.
Rodent behavioural tests were based on reversal of hyperactivity induced by psychostimulants and on measures of induction of catalepsy and 'serotonin syndrome'.
F15063 potently (ED(50)s: 0.23 to 1.10 mg kg(-1) i.p.) reversed methylphenidate-induced stereotyped behaviors, blocked d-amphetamine and ketamine hyperlocomotion, attenuated apomorphine-induced prepulse inhibition (PPI) deficits, and was active in the conditioned avoidance test. In mice, it reversed apomorphine-induced climbing (ED(50)=0.30 mg kg(-1) i.p.). F15063, owing to its 5-HT(1A) agonism, did not produce (ED(50)>40 mg kg(-1) i.p.) catalepsy in rats and mice, a behavior predictive of occurrence of extra-pyramidal syndrome (EPS) in man. This absence of cataleptogenic activity was maintained upon sub-chronic treatment of rats for 5 days at 40 mg kg(-1) p.o. Furthermore, F15063 did not induce the 'serotonin syndrome' in rats (flat body posture and forepaw treading: ED(50) >32 mg kg(-1) i.p.).
F15063 conformed to the profile of an atypical antipsychotic, with potent actions in models of hyperdopaminergic activity but without inducing catalepsy. These data suggest that F15063 may display potent antipsychotic actions with low EPS liability. This profile is complemented by a favourable profile in rodent models of negative symptoms and cognitive deficits of schizophrenia (companion paper).
British Journal of Pharmacology 06/2007; 151(2):253-65. DOI:10.1038/sj.bjp.0707159 · 4.84 Impact Factor
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