Piracetam in the treatment of schizophrenia: implications for the glutamate hypothesis of schizophrenia

Noorbala, Ahmad-Ali; Akhondzadeh, Shahin; Davari-Ashtiani, Rozita; Amini-Nooshabadi, H.

doi:10.1046/j.1365-2710.1999.00238.x

Cited by 61 publications

(31 citation statements)

References 38 publications

(46 reference statements)

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“…As we described in our study, pharmacological, anatomical, and genetic information indicate that deficits in glutamatergic neurotransmission, particularly those mediated by NMDA receptors, may be a contributor to all three symptom clusters (Akhondzadeh 1998). Although reduced corticostriatal transmission may specifically contribute to an apparent hyperdopaminergia and psychotic symptoms, the downstream consequences of such a disruption may also contribute to the negative and cognitive symptoms of schizophrenia (Noorbala et al 1999). Indeed, Siuciak concluded in their review that PDE inhibitors "may be effective in treating positive symptoms, negative symptoms and/or cognitive deficits associated with schizophrenia" (Siuciak 2008).…”

supporting

confidence: 51%

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Akhondzadeh

Ghayyoumi

2011

Psychopharmacology

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supporting

confidence: 51%

Author reply

Akhondzadeh

Ghayyoumi

2011

Psychopharmacology

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“…AMPAkines have little effect on spontaneous locomotor activity in intact animals but can suppress methamphetamine-induced hyperactivity in rats (34)(35)(36). The emerging evidence of the involvement of the glutamatergic system in certain manifestations of schizophrenia (10-13, 37, 38, 57, 67) provides a theoretical basis to explore the potential therapeutical benefit of AMPAkines in this disorder (34)(35)(36)68). The efficacy of these drugs in counteracting dopaminergic hyperactivity suggests that AMPAkines also could potentially be effective in treating dopamine related symptoms of this disorder as well as other conditions resulting primarily from dopaminergic dysfunctions.…”

Section: Discussionmentioning

confidence: 99%

Glutamatergic modulation of hyperactivity in mice lacking the dopamine transporter

Gainetdinov

Mohn

Bohn

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

152

109

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In the brain, dopamine exerts an important modulatory influence over behaviors such as emotion, cognition, and affect as well as mechanisms of reward and the control of locomotion. The dopamine transporter (DAT), which reuptakes the released neurotransmitter into presynaptic terminals, is a major determinant of the intensity and duration of the dopaminergic signal. Knockout mice lacking the dopamine transporter (DAT-KO mice) display marked changes in dopamine homeostasis that result in elevated dopaminergic tone and pronounced locomotor hyperactivity. A feature of DAT-KO mice is that their hyperactivity can be inhibited by psychostimulants and serotonergic drugs. The pharmacological effect of these drugs occurs without any observable changes in dopaminergic parameters, suggesting that other neurotransmitter systems in addition to dopamine might contribute to the control of locomotion in these mice. We report here that the hyperactivity of DAT-KO mice can be markedly further enhanced when N-methyl-D-aspartate receptor-mediated glutamatergic transmission is blocked. Conversely, drugs that enhance glutamatergic transmission, such as positive modulators of L-␣-amino-3-hydroxy-5-methylisoxazole-4-propionate glutamate receptors, suppress the hyperactivity of DAT-KO mice. Interestingly, blockade of Nmethyl-D-aspartate receptors prevented the inhibitory effects of both psychostimulant and serotonergic drugs on hyperactivity. These findings support the concept of a reciprocal functional interaction between dopamine and glutamate in the basal ganglia and suggest that agents modulating glutamatergic transmission may represent an approach to manage conditions associated with dopaminergic dysfunction. F rontostriatal circuitry is one of the most prominent brain pathways involved in the control of locomotion, affect, impulsivity, attention, and emotion (1, 2). One axis of this circuitry involves dopaminergic projections into the striatal and mesolimbic brain areas (1, 3). Dopaminergic transmission has been intensively studied and is relatively well characterized (1, 3), largely because alterations in dopaminergic tone have clear behavioral manifestations such as changes in locomotor activity. In addition to dopaminergic innervation from substantia nigra and ventral tegmental area, the basal ganglia receive dense glutamatergic input predominantly from prefrontal cortical areas, as well as from the hippocampus, periventricular thalamus, and amygdala (1, 4, 5). There is a growing appreciation for the concept that dopaminergic and glutamatergic systems intimately interact at the level of medium-sized spiny neurons in the basal ganglia to control behavior (1, 6, 7). Particularly, an interaction at the levels of receptor signaling and regulation between dopamine D1 and͞or D2-like receptors and ionotropic glutamate N-methyl-D-aspartate (NMDA) and L-␣-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors, has been put forth (7-9). Recent findings in mice with decreased NMDA receptor expression (10) confirmed and extended pr...

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“…Hippocampal CA1 and CA3 cell firing measured during DNMS testing revealed an increase of 100-350% with CX516, which was restricted to correct trials and paralleled the time course of the improvement in performance (Hampson et al, 1998). Noorbala et al (1999) were the first to study an Ampakine in schizophrenia when they administered the weak AMPAreceptor-positive modulator, piracetam, combined with open-label haloperidol to 30 medication-free schizophrenia patients in a placebo-controlled, 8-week trial. Piracetam significantly improved psychotic symptoms, but did not improve negative symptoms or the PANSS total score compared to placebo.…”

Section: Introductionmentioning

confidence: 97%

A Placebo-Controlled Add-On Trial of the Ampakine, CX516, for Cognitive Deficits in Schizophrenia

Goff

Lamberti

Leon

et al. 2007

Neuropsychopharmacol

163

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AMPA-receptor-positive modulators (Ampakines) facilitate learning and memory in animal models and in preliminary trials in human subjects. CX516 is the first Ampakine to be studied for cognitive enhancement in schizophrenia. Stable schizophrenia patients treated with clozapine (n ¼ 52), olanzapine (n ¼ 40), or risperidone (n ¼ 13) were randomly assigned to add-on treatment with CX516 900 mg three times daily or placebo for 4 weeks. Subjects were assessed with a cognitive battery at baseline, week 4, and at 4-week follow-up. Clinical scales and safety monitoring were also performed. The primary endpoint was the change from baseline in a composite cognitive score at week 4 for the intent-to-treat sample. Additional analyses examined change in symptom rating scores and examined drug effects on patients treated with clozapine separately from patients treated with either olanzapine or risperidone. A total of 105 patients were randomized and 95 (90%) completed the 4-week trial. Patients treated with CX516 did not differ from placebo in change from baseline on the composite cognitive score, or on any cognitive test at weeks 4 or 8. The between groups effect size at week 4 for the cognitive composite score was À0.19 for clozapine-treated patients and 0.24 for patients treated with olanzapine or risperidone. The placebo group improved more on the PANSS total score than the CX516 group; no other clinical rating differed between treatment groups. CX516 was associated with fatigue, insomnia and epigastric discomfort compared to placebo, but was generally well tolerated. CX516 was not effective for cognition or for symptoms of schizophrenia when added to clozapine, olanzapine, or risperidone.

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Piracetam in the treatment of schizophrenia: implications for the glutamate hypothesis of schizophrenia

Abstract: Piracetam, a member of the nootropic class of drugs and a positive modulator of glutamate receptor, may be of therapeutic benefit in treating schizophrenic patients in combination with typical neuroleptics. However, a larger study to confirm our results is warranted

Cited by 61 publications

References 38 publications

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Glutamatergic modulation of hyperactivity in mice lacking the dopamine transporter

A Placebo-Controlled Add-On Trial of the Ampakine, CX516, for Cognitive Deficits in Schizophrenia

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