Clozapine Plus Lamotrigine in Treatment-Resistant Schizophrenia

Dursun, Serdar; McIntosh, Diane; Milliken, Heather

doi:10.1001/archpsyc.56.10.950

Cited by 86 publications

(36 citation statements)

References 3 publications

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“…The reduction of general psychopathology during lamotrigine add-on treatment in schizophrenic patients has been documented in previous open trials (Dursun et al, 1999;Dursun and Deakin, 2001), brief reports (Kolivakis et al, 2004;Thomas et al, 2006), and randomized, double-blind, placebo-controlled trials (Tiihonen et al, 2003;Kremer et al, 2004). Besides the efficacy on general psychopathology, the results by Tiihonen et al (2003) indicated that lamotrigine combined with clozapine significantly improved positive symptoms; similar findings emerged from the placebocontrolled trial by Kremer et al (2004) which showed that positive symptoms and general psychopathology scores continued to decrease also during the 2-week fixed dose treatment with 400 mg/day.…”

Section: Discussionmentioning

confidence: 74%

“…Moreover, it can be considered a potentially confusing element, as the improvement in clinical symptomatology reported after lamotrigine add-on therapy may result from an increase of clozapine plasma concentrations. As suggested by Dursun et al (1999) on the basis of the observation that lamotrigine is metabolized in the liver by glucuronidation whereas clozapine is mainly metabolized by the isoenzyme 1A2 of the CPYP450 system, any interaction between the two drugs was expected to be pharmacodynamic rather than kinetic. Consistent with this hypothesis, a recent study performed on a sample of 35 schizophrenic patients (Spina et al, 2006) showed that lamotrigine, at the dosages recommended for use as a mood stabilizer (up to 200 mg/day) had little or no effect on the pharmacokinetics of the investigated antipsychotics.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies with lamotrigine added to clozapine in refractory schizophrenic patients have reported promising results, such as the significant BPRS score reduction in partially responding or treatment-resistant schizophrenic patients on clozapine (Saba et al, 2002;Dursun et al, 1999). In a naturalistic follow-up case series (Dursun and Deakin, 2001), lamotrigine added to ongoing antipsychotic treatments at doses ranging from 100 to 300 mg/day improved BPRS total scores only in clozapine-treated patients.…”

Section: Introductionmentioning

confidence: 98%

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The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: A double-blind, placebo-controlled study

Zoccali

Muscatello

Bruno

et al. 2007

Schizophrenia Research

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Based on the evidence that lamotrigine added to clozapine in refractory schizophrenic patients has reported promising results, the present 24-week double-blind, randomized, placebo-controlled trial had the aim to explore the efficacy of lamotrigine add-on pharmacotherapy on clinical symptomatology and cognitive functioning in a sample of treatment-resistant schizophrenic patients receiving clozapine. After clinical and neurocognitive assessments patients were randomly allocated to receive, in a double-blind design, either up to 200 mg/day of lamotrigine or a placebo. A final sample of fifty-one patients completed the study.The results obtained indicate that lamotrigine added to stable clozapine treatment showed a beneficial effect on the negative, positive and general psychopathological symptomatology in a sample of treatment-resistant schizophrenic patients. Regarding cognitive functions, improvement was observed in some explored areas, such as attentional resistance to interference, verbal fluency and executive functioning. The findings provide evidence that lamotrigine augmentation of clozapine treatment is well tolerated and may be proposed as an effective therapeutic strategy to improve outcome in treatment-resistant schizophrenia.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: A double-blind, placebo-controlled study

Zoccali

Muscatello

Bruno

et al. 2007

Schizophrenia Research

View full text Add to dashboard Cite

show abstract

“…120 Lamotrigine, an antiepileptic that reduces presynaptic glutamate release, has also been proposed as a potential adjunctive medication in schizophrenia. 121,122 In humans, lamotrigine prevented acute psychotomimetic effects of ketamine, with greater effects on positive than negative symptoms. 121 Improvements in positive and general symptoms have been reported as well in small-scale studies of lamotrigine in clozapine-treated patients with persistent clinical symptoms.…”

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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“…A clinical trial demonstrated that administration of LTG along with stable clozapine elicited 4 beneficial effects on the psychopathological symptoms of clozapine-resistant schizophrenic patients [7,8,23]. Furthermore, LTG pretreatment prevents regional blood oxygenation level-dependent (BOLD) signal changes and psychotic symptoms induced by ketamine in healthy men [6].…”

Section: Introductionmentioning

confidence: 99%