d-Cycloserine added to risperidone in patients with primary negative symptoms of schizophrenia

Evins, A. Eden; Amico, E. T.; Posever, Thomas; Toker, Rob; Goff, Donald C.

doi:10.1016/s0920-9964(01)00220-1

Cited by 102 publications

(44 citation statements)

References 21 publications

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“…There were 27 randomized placebo-controlled doubleblind studies (2,6,7,10-12,14,23,25-42), 8 non-randomized trials (43)(44)(45)(46)(47)(48)(49)(50)(51), and 1 case report. Except for two trials (42,49) with drug-free patients, all other studies involved adjuvant therapy for antipsychotic treatment.…”

Section: Resultsmentioning

confidence: 99%

Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update

Chaves

Marque

Trzesniak

et al. 2009

Braz J Med Biol Res

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Section: Resultsmentioning

confidence: 99%

Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update

Chaves

Marque

Trzesniak

et al. 2009

Braz J Med Biol Res

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“…An interaction between clozapine and the a7* nicotinic receptor is supported by the demonstration of a clozapine-induced release of acetylcholine in the prefrontal cortex (Ichikawa et al, 2002). In favor of an interaction by clozapine with glutamatergic mechanisms, treatment augmentation studies with agents acting at the glycine-site of the NMDA receptor have shown that glycine and Dcycloserine improve negative symptoms when added to conventional antipsychotic drugs, but not when added to clozapine (Evins et al, 2002;Goff et al, 1999, Heresco-Levy et al, 1998Javitt et al, 1994;Tsai et al, 1998). This indicates that clozapine may be an agonist or partial agonist at the glycine-site of the NMDA receptor or an inhibitor of the glycine transporter and such actions may contribute to its unique clinical efficacy.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Action of Clozapine on Rat Ventral Tegmental Area Dopamine Neurons Following Increased Levels of Endogenous Kynurenic Acid

Schwieler

Erhardt

2003

Neuropsychopharmacol

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The mode of action by which the atypical antipsychotic drug clozapine exerts its superior efficacy to ameliorate both positive and negative symptoms is still unknown. In the present in vivo electrophysiological study, we investigate the effects of haloperidol (a typical antipsychotic drug) and clozapine on ventral tegmental area (VTA) dopamine (DA) neurons in a situation of hyperdopaminergic activity in order to mimic tentatively a condition similar to that seen in schizophrenia. Increased DA transmission was induced by elevating endogenous levels of the N-methyl-D-aspartate receptor and a7* nicotinic receptor antagonist kynurenic acid (KYNA; by means of PNU 156561A, 40 mg /kg, i.v.). In control rats, i.v. administered haloperidol (0.05-0.8 mg/kg) or clozapine (1.25-10 mg/kg) was associated with increased firing rate and burst firing activity of VTA DA neurons. However, in rats displaying hyperdopaminergia (induced by elevated levels of KYNA), the effects of clozapine on VTA DA neurons were converted into pure inhibitory responses, including decrease in burst firing activity. In contrast, haloperidol still produced an excitatory action on VTA DA neurons in rats with elevated levels of endogenous brain KYNA. The results of the present study suggest that clozapine facilitates or inhibits VTA DA neurotransmission, depending on brain concentration of KYNA. Such an effect of clozapine may be related to its unique effect in also ameliorating negative symptoms of schizophrenia.

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“…For example, recent studies, some of them double blind and placebo-controlled, have shown that d-cycloserine, glycine, and d-serine improve some aspects of negative symptomatology and cognitive dysfunction, do not interfere with the beneficial effects of antipsychotics on the positive symptomatology and are also well tolerated (Goff et al, 1995(Goff et al, , 1999Tsai et al, 1998;Heresco-Levy et al, 1998, 2002Javitt et al, 2001;Evins et al, 2002). Beneficial effects on negative symptomatology and cognitive dysfunction are of interest, as current antipsychotics are marginally effective against these two aspects of the pathology.…”

Section: Introductionmentioning

confidence: 99%

Neurochemical, Electrophysiological and Pharmacological Profiles of the Selective Inhibitor of the Glycine Transporter-1 SSR504734, a Potential New Type of Antipsychotic

Depoortère

Dargazanli

Estenne-Bouhtou

et al. 2005

Neuropsychopharmacol

216

161

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Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC 50 ¼ 18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID 50 : 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 mM) and intrastriatal glycine-induced rotations in mice (MED: 1 mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB 1 receptors): it reversed the decrease in electrically evoked [3 H]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.

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d-Cycloserine added to risperidone in patients with primary negative symptoms of schizophrenia

Cited by 102 publications

References 21 publications

Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update

Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update

Inhibitory Action of Clozapine on Rat Ventral Tegmental Area Dopamine Neurons Following Increased Levels of Endogenous Kynurenic Acid

Neurochemical, Electrophysiological and Pharmacological Profiles of the Selective Inhibitor of the Glycine Transporter-1 SSR504734, a Potential New Type of Antipsychotic

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