Efficacy of newer generation antipsychotics in the treatment of schizophrenia

Tandon, Rajiv; Jibson, Michael D.

doi:10.1016/s0306-4530(02)00110-5

Cited by 138 publications

(62 citation statements)

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“…Based on their propensity to induce extrapyramidal symptoms (EPSs), ADP drugs can be classified as typical or atypical (Tandon and Jibson, 2003;Meltzer, 2004). The molecular mechanisms responsible for the differences in the clinical profile of typical and atypical APDs remain unclear.…”

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confidence: 99%

Haloperidol and Clozapine Differentially Affect the Expression of Arrestins, Receptor Kinases, and Extracellular Signal-Regulated Kinase Activation

Ahmed

Gurevich

Dalby³

et al. 2008

J Pharmacol Exp Ther

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Dopamine and other G protein-coupled receptors (GPCRs) represent the major target of antipsychotic drugs. GPCRs undergo desensitization via activation-dependent phosphorylation by G protein-coupled receptor kinases (GRKs) followed by arrestin binding. Arrestins and GRKs are major regulators of GPCR signaling. We elucidated changes in expression of two arrestins and four GRKs following chronic (21 days) treatment with haloperidol (1 mg/kg i.p.) or clozapine (20 mg/kg i.p.) 2 or 24 h after the last injection in 11 brain regions. Haloperidol decreased GRK3 in ventrolateral caudate-putamen and transiently down-regulated GRK5 in globus pallidus and caudal caudate-putamen. Clozapine also caused a short-term suppression of the GRK5 expression in the caudal caudate-putamen and globus pallidus, but, unlike haloperidol, elevated GRK5 in the caudal caudate-putamen after 24 h. Unlike haloperidol, clozapine decreased arrestin2 and GRK3 in hippocampus and GRK3 in globus pallidus but increased arrestin2 in the core of nucleus accumbens and ventrolateral caudate-putamen and GRK2 in prefrontal cortex. Clozapine, but not haloperidol, induced long-term activation of extracellular signalregulated kinase (ERK) 2 in ventrolateral caudate-putamen and transient in prefrontal cortex. The data demonstrate that haloperidol and clozapine differentially affect the expression of arrestins and GRKs and ERK activity, which may play a role in determining their clinical profile.

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confidence: 99%

Haloperidol and Clozapine Differentially Affect the Expression of Arrestins, Receptor Kinases, and Extracellular Signal-Regulated Kinase Activation

Ahmed

Gurevich

Dalby³

et al. 2008

J Pharmacol Exp Ther

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“…However, these differences seem to be quantitative rather than qualitative (Lieberman et al, 2005). Large clinical trials as well as systematic and critical reviews confirm that antipsychotics carry comparable side-effect burdens (Rummel et al, 2003;Tandon and Jibson, 2003).…”

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confidence: 99%

Antipsychotic-Like Properties of Phosphodiesterase 4 Inhibitors: Evaluation of 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone (RO-20-1724) with Auditory Event-Related Potentials and Prepulse Inhibition of Startle

Halene¹,

Siegel²

2008

J Pharmacol Exp Ther

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Antipsychotic medications function through antagonism of D2 dopamine receptors. Blockade of D2 receptors causes an increase in intracellular cAMP, a ubiquitous second messenger. Inhibition of phosphodiesterase (PDE) activity, a family of enzymes that degrade cyclic nucleotides, causes the same effect. The conceptual linkage between dopamine D2 receptors and PDE activity via cAMP suggests a possible therapeutic potential for PDE inhibitors in schizophrenia. The limited number of studies in support of this hypothesis used rolipram, a specific inhibitor of the PDE4 family. In this study, we investigated the impact of 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO-20-1724), another PDE4-specific inhibitor, on auditory event-related potentials (ERPs), prepulse inhibition (PPI) of the startle reflex, and locomotor activity in mice. The ability to reverse amphetamine-induced alterations in ERPs and PPI was used as a model for psychosis. ERPs after RO-20-1724 revealed increased amplitude for the P20 and N40 ERP components. RO-20-1724 reversed the disruptive effect of amphetamines on ERPs and restored gating at a dose that did not impair locomotor activity. However, RO-20-1724 failed to reverse a amphetamine-induced decrease of PPI. Inconsistent results between these two psychosis models suggest that pure sensory processing, as measured with auditory ERPs, may be more sensitive to the effects of intracellular cAMP than sensorimotor effects as assessed with PPI. It remains unclear whether antipsychotic-like properties are a common feature of PDE4 inhibition, or if they are restricted to the pharmacological profile of rolipram. Future studies should examine how PDE4 subtype specificity might contribute to differences between rolipram and RO-20-1724 in sensorimotor gating.Antipsychotic medications were introduced more than 50 years ago for the treatment of hallucinations, delusions, thought disorganization, and behavioral disorders. Although initially targeted for the treatment of schizophrenia, these medications act on psychotic symptoms irrespective of cause. Currently approved antipsychotic medications produce their beneficial effects through antagonism of the dopamine D2 receptor. Their potency is proportional to their affinity for this target (Kapur and Mamo, 2003). Blockade of D2 receptors causes an increase in intracellular cAMP, a ubiquitous second messenger. Inhibition of phosphodiesterase (PDE) activity, a family of enzymes with the ability to degrade cyclic nucleotides, causes the same effect. The conceptual linkage between the dopamine D2 receptor and PDE activity via cAMP suggests a possible therapeutic potential for PDE inhibitors in schizophrenia (Fig. 1).No single antipsychotic substance has emerged as the gold standard for a first-line treatment in clinical trials or expert consensus guidelines, and with the notable exception of clozapine, all approved antipsychotics are of comparable efficacy. Antipsychotics vary in side effects including risk of extrapyramidal symptoms, weight gain, metabolic ...

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“…Although the probability of becoming minimally symptomatic varied between the atypical antipsychotic treatment groups, the likelihood of patients achieving a minimally symptomatic status was greater in younger patients with lower baseline clinical severity and in patients whose treatment included olanzapine. (13)(14)(15)(16)(17). The course and ⁄ or outcome measurements in studies of schizophrenia have included global assessment scales, such as Clinical Global Impression-Severity in Schizophrenia (CGI-SCH), and symptom domain-specific scales, such as the Scale for the Assessment of Negative Symptoms, and the assessment of functional status such as occupation and social relationships.…”

Section: What's Newmentioning

confidence: 99%

Factors associated with achieving minimally symptomatic status by patients with schizophrenia: results from the 3-year intercontinental schizophrenia outpatients health outcomes study

Treuer¹,

Martényi

Şaylan³

et al. 2010

International Journal of Clinical Practice

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Summary Objective: The aim of this study was to describe factors associated with achieving a minimally symptomatic status outcome in outpatients with schizophrenia. Methods: Data were analysed from a 3‐year, prospective observational study that examined outcomes in 7658 patients with schizophrenia. Minimally symptomatic status was defined as a postbaseline score of 1 or 2 on the Clinical Global Impressions Severity Scale‐Schizophrenia version (CGI‐SCH). Results: Baseline CGI‐SCH score had the strongest association with minimally symptomatic status followed by age, geographical region and hospitalisation status. The probability of becoming minimally symptomatic was consistently higher in the olanzapine and clozapine monotherapy groups compared with the quetiapine, risperidone or haloperidol groups. The olanzapine group achieved the minimally symptomatic status in a shorter period of time than the other treatment groups (p ≤ 0.016). Conclusion: The likelihood of patients achieving a minimally symptomatic status was greater in younger patients with lower baseline clinical severity and in patients whose treatment included olanzapine.

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Efficacy of newer generation antipsychotics in the treatment of schizophrenia

Cited by 138 publications

References 50 publications

Haloperidol and Clozapine Differentially Affect the Expression of Arrestins, Receptor Kinases, and Extracellular Signal-Regulated Kinase Activation

Haloperidol and Clozapine Differentially Affect the Expression of Arrestins, Receptor Kinases, and Extracellular Signal-Regulated Kinase Activation

Antipsychotic-Like Properties of Phosphodiesterase 4 Inhibitors: Evaluation of 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone (RO-20-1724) with Auditory Event-Related Potentials and Prepulse Inhibition of Startle

Factors associated with achieving minimally symptomatic status by patients with schizophrenia: results from the 3-year intercontinental schizophrenia outpatients health outcomes study

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