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
"Currently available antipsychotics control the so-called positive symptoms of schizophrenia (hallucination, delusions , etc) in about two-thirds of patients treated, reflecting their antagonist properties at dopamine D 2 receptors (Kapur and Remington, 2001). Other aspects of the pathology, such as negative symptoms (flat affect, avolition, anergia, etc) and cognitive dysfunction (including working memory impairment , perseveration and attention deficits) are also alleviated but to a more limited extent (Tandon et al., 1993, Breier et al., 1994, Buchanan et al., 1998, Rosenheck et al., 1999). These cognitive deficits are increasingly considered to be part of the core symptoms of the pathology and the limited efficacy of antipsychotics to combat them hampers proper societal functioning of patients and their reinsertion (Freedman, 2003; Green et al., 2004), and constitutes a real challenge to clinicians. "
[Show abstract][Hide abstract] ABSTRACT: The D(2)/D(3) receptor antagonist, D(4) receptor partial agonist, and high efficacy 5-HT(1A) receptor agonist F15063 was shown to be highly efficacious and potent in rodent models of activity against positive symptoms of schizophrenia. However F15063 induced neither catalepsy nor the 'serotonin syndrome'. Here, we evaluated its profile in rat models predictive of efficacy against negative symptoms/cognitive deficits of schizophrenia.
F15063, given i.p., was assessed in models of behavioural deficits induced by interference with the NMDA/glutamatergic (phencyclidine: PCP) or cholinergic (scopolamine) systems.
Through 5-HT(1A) activation, F15063 partially alleviated (MED: 0.04 mg kg(-1)) PCP-induced social interaction deficit between two adult rats, without effect by itself, underlining its potential to combat negative symptoms. At doses above 0.16 mg kg(-1), F15063 reduced interaction by itself. F15063 (0.16 mg kg(-1)) selectively re-established PCP-impaired 'cognitive flexibility' in a reversal learning task, suggesting potential against adaptability deficits. F15063 (0.04-0.63 mg kg(-1)) also reversed scopolamine-induced amnesia in a juvenile-adult rat social recognition test, indicative of a pro-cholinergic influence. Activity in this latter test is consistent with its D(4) partial agonism, as it was blocked by the D(4) antagonist L745,870. Finally, F15063 up to 40 mg kg(-1) did not disrupt basal prepulse inhibition of startle reflex in rats, a marker of sensorimotor gating.
The balance of D(2)/D(3), D(4) and 5-HT(1A) receptor interactions of F15063 yields a promising profile of activity in models of cognitive deficits and negative symptoms of schizophrenia.
British Journal of Pharmacology 06/2007; 151(2):266-77. DOI:10.1038/sj.bjp.0707160 · 4.84 Impact Factor
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