A Placebo-Controlled Pilot Study of the Ampakine CX516 Added to Clozapine in Schizophrenia

Goff, Donald C.; Leahy, Leslie; Berman, Ileana; Posever, Thomas; Herz, Lawrence; Leon, Andrew C.; Johnson, Steven A.; Lynch, Gary

doi:10.1097/00004714-200110000-00005

Cited by 205 publications

(122 citation statements)

References 13 publications

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“…In this study, significant improvements in memory and attention were observed despite lack of symptomatic improvement. 118 CX-516 has also been studied as monotherapy, with no clear beneficial effects. 119 Although downregulation of AMPA receptors is less with AMPAkines than with direct agonists, there is some concern that downregulation may nonetheless occur and may limit long-term treatment strategies.…”

Section: Other Ionotropic Targetsmentioning

confidence: 99%

Glutamate as a therapeutic target in psychiatric disorders

2004

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Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic neurotransmission may be modulated at multiple levels, only a minority of which are currently being exploited for pharmaceutical development. Ionotropic receptors for glutamate are divided into N-methyl-D-aspartate receptor (NMDAR) and AMPA receptor subtypes. NMDAR have been implicated in the pathophysiology of schizophrenia. The glycine modulatory site of the NMDAR is currently a favored therapeutic target, with several modulatory agents currently undergoing clinical development. Of these, the full agonists glycine and D-serine have both shown to induce significant, large effect size reductions in persistent negative and cognitive symptoms when added to traditional or newer atypical antipsychotics in double-blind, placebo-controlled clinical studies. Glycine (GLYT1) and small neutral amino-acid (SNAT) transporters, which regulate glycine levels, represent additional targets for drug development, and may represent a site of action of clozapine. Brain transporters for D-serine have recently been described. Metabotropic glutamate receptors are positively (Group I) or negatively (Groups II and III) coupled to glutamatergic neurotransmission. Metabotropic modulators are currently under preclinical development for neuropsychiatric conditions, including schizophrenia, depression and anxiety disorders. Other conditions for which glutamate modulators may prove effective include stroke, epilepsy, Alzheimer disease and PTSD. Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Approximately 60% of neurons in the brain, including all cortical pyramidal neurons and thalamic relay neurons, utilize glutamate as their primary neurotransmitter. 1 As a result, virtually all thalamocortical, corticocortical and corticofugal neurotransmission in the brain is mediated by glutamate. Glutamate is released from presynaptic terminals in response to neuronal depolarization, and is recycled by excitatory amino acid (EAA) transporters located on both neurons and glia. 2 Within glia, glutamate is converted to glutamine and released into extracellular fluid from which it is reabsorbed into presynaptic terminals and converted back to glutamate via action of neuronal glutaminase. Up to 2/3 of brain energy metabolism is related to reuptake and recycling of glutamate. 3 As such, functional imaging modalities, such as PET and fMRI, indexing activity primarily of brain glutamatergic systems. 4 The exchange of glutamine from glia to neurons is accomplished by coordinated actions of two transport systems, systems N and A, both of which are members of sodium-dependent neutral amino acid (SNAT) family of transporters. 5 These transport systems also transport precursors for cysteine and glycine, which are precursors to glutathione synthesis. 6 As these transporters are electrogenic, glutamate transporters may also participate in cellular signaling. 7 As with glutamate and GABA transporters, these recycling systems may constitute interesti...

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Section: Other Ionotropic Targetsmentioning

confidence: 99%

Glutamate as a therapeutic target in psychiatric disorders

2004

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“…Furthermore, preliminary human studies have suggested that ampakines may have a positive memory encoding effect with respect to visual associations, recognition of odors, acquisition of a visuospatial maze, location and identity of playing cards (Ingvar et al 1997), and enhances delayed recall in older individuals (Lynch et al 1997). Finally, in very preliminary studies of schizophrenic patients, CX516 was added to clozapine in 4-week, placebo-controlled, dose-finding and fixed-dose trials and was suggested to exert beneficial effects in measures of attention and memory (Goff et al 2001). An investigation of CNS-penetrant AMPA modulating agents in the treatment of depression is clearly warranted.…”

Section: The Glutamatergic System As a Target For Novel Antidepressanmentioning

confidence: 99%

Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for Difficult-to-Treat depression

Manji

Quiróz

Sporn

et al. 2003

Biological Psychiatry

445

259

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“…One was a double-blind placebo-controlled trial in which CX516 was added to clozapine treatment for 4 weeks ((19 patients in total: 12 were allocated to CX516 treatment and seven to the placebo treatment group) Goff et al, 2001). The ampakine group showed moderate to large improvements compared to the placebo group on attention and memory performance and showed a reduction of negative symptoms.…”

Section: Introductionmentioning

confidence: 99%

Acute Effects of the Ampakine Farampator on Memory and Information Processing in Healthy Elderly Volunteers

Wezenberg

Verkes

Ruigt³

et al. 2006

Neuropsychopharmacol

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Ampakines act as positive allosteric modulators of AMPA-type glutamate receptors and facilitate hippocampal long-term potentiation (LTP), a mechanism associated with memory storage and consolidation. The present study investigated the acute effects of farampator, 1-(benzofurazan-5-ylcarbonyl) piperidine, on memory and information processes in healthy elderly volunteers. A double-blind, placebocontrolled, randomized, cross-over study was performed in 16 healthy, elderly volunteers (eight male, eight female; mean age 66.1, SD 4.5 years). All subjects received farampator (500 mg) and placebo. Testing took place 1 h after drug intake, which was around T max for farampator. Subjects performed tasks assessing episodic memory (wordlist learning and picture memory), working and short-term memory (N-back, symbol recall) and motor learning (maze task, pursuit rotor). Information processing was assessed with a tangled lines task, the symbol digit substitution test (SDST) and the continuous trail making test (CTMT). Farampator (500 mg) unequivocally improved short-term memory but appeared to impair episodic memory. Furthermore, it tended to decrease the number of switching errors in the CTMT. Drug-induced side effects (SEs) included headache, somnolence and nausea. Subjects with SEs had significantly higher plasma levels of farampator than subjects without SEs. Additional analyses revealed that in the farampator condition the group without SEs showed a significantly superior memory performance relative to the group with SEs. The positive results on short-term memory and the favorable trends in the trail making test (CTMT) are interesting in view of the development of ampakines in the treatment of Alzheimer's disease and schizophrenia.

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A Placebo-Controlled Pilot Study of the Ampakine CX516 Added to Clozapine in Schizophrenia

Cited by 205 publications

References 13 publications

Glutamate as a therapeutic target in psychiatric disorders

Glutamate as a therapeutic target in psychiatric disorders

Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for Difficult-to-Treat depression

Acute Effects of the Ampakine Farampator on Memory and Information Processing in Healthy Elderly Volunteers

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