Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled trials.

OBJECTIVE: : Lamotrigine previously was found to attenuate ketamine-induced behavioral changes and, in 2 placebo-controlled trials, to improve psychosis when added to antipsychotic medication. We sought to evaluate the potential role of lamotrigine augmentation in schizophrenia patients resistant to atypical antipsychotic medication. METHODS: : Two multicenter, randomized, double-blind, 12-week, parallel-group trials were conducted to compare flexibly dosed lamotrigine (100-400 mg/d) with placebo as add-on treatment in schizophrenia patients with stable, residual psychotic symptoms. The primary end point was changed in Positive and Negative Syndrome Scale total score at week 12. RESULTS: : Two hundred seventeen patients were enrolled in study 1 and 212 in study 2; completion rates in the intent-to-treat samples were 71% and 74%, respectively, and did not differ between treatment groups. Overall, mean Positive and Negative Syndrome Scale total scores improved in both studies and did not differ between treatment groups. In study 1, the Scale for Assessment of Negative Symptoms total score and Clinical Global Impression improved more with placebo than with lamotrigine; in study 2, the cognitive composite score improved more with lamotrigine than with placebo. CONCLUSIONS: : Results from these 2 studies do not support the use of lamotrigine as an adjunct to atypical antipsychotics in patients with refractory psychosis. It is unclear why positive results from previous lamotrigine trials were not replicated. The positive effect of lamotrigine on cognition in one trial, while of uncertain significance, may merit further study.

The potential role of lamotrigine in schizophrenia.

RATIONALE: Atypical antipsychotic drugs are the drugs of choice for the treatment of schizophrenia. However, despite advances, no treatments have been established for patients who fail to improve with the most effective of these, clozapine. The inhibition of dopamine transmission through blockade of dopamine D2 receptors is considered to be essential for antipsychotic efficacy, but it is postulated that modulation of glutamate transmission may be equally important. In support of this, symptoms similar to schizophrenia can be induced in healthy volunteers using N-methyl-D-aspartate (NMDA) antagonist drugs that are also known to enhance glutamate transmission. Furthermore, lamotrigine, which can modulate glutamate release, may add to or synergise with atypical antipsychotic drugs, some of which may themselves modulate glutamate transmission. OBJECTIVES: We examine the evidence for the efficacy of lamotrigine. We consider how this fits with a glutamate neuron dysregulation hypothesis of the disorder. We discuss mechanisms by which lamotrigine might influence neuronal activity and glutamate transmission, and possible ways in which the drug might interact with antipsychotic medications. RESULTS: Data from four clinical studies support the efficacy of adjunctive lamotrigine in the treatment of schizophrenia. In addition, and consistent with a glutamate neuron dysregulation hypothesis of schizophrenia, lamotrigine can prevent the psychotic symptoms or behavioural disruption induced by NMDA receptor antagonists in healthy volunteers or rodents. CONCLUSIONS: The efficacy of lamotrigine is most likely explained within the framework of a glutamate neuron dysregulation hypothesis, and may arise primarily through the drugs ability to influence glutamate transmission and neural activity in the cortex. The drug is likely to act through inhibition of voltage-gated sodium channels, though other molecular interactions cannot be ruled out. Lamotrigine may add to or synergise with some atypical antipsychotic drugs acting on glutamate transmission; alternatively, they may act independently on glutamate and dopamine systems to bring about a combined therapeutic effect. We propose new strategies for the treatment of schizophrenia using a combination of anti-dopaminergic and anti-glutamatergic drugs.

Corticotropin releasing hormone (CRH) antagonist attenuates adjuvant induced arthritis: role of CRH in peripheral inflammation.

OBJECTIVE: To determine whether a corticotropin releasing hormone (CRH) type 1-specific receptor antagonist, antalarmin, would alter the progression of inflammation in adjuvant induced arthritis (AIA) susceptible LEW/N rats by blocking local CRH mediated inflammatory responses or render AIA resistant F344/N rats more susceptible to AIA by blocking central CRH, thus reducing secretion of endogenous glucocorticoids. METHODS: F344/N and LEW/N rats were assigned to either drug or vehicle groups and treated with 20 mg/kg antalarmin or vehicle alone BID for 25 days by intraperitoneal injection. Arthritis was induced in both antalarmin and vehicle treated LEW/N and F344/N rats by subcutaneous injections at the base of the tail of incomplete Freund's adjuvant containing 10 mg/ml heat killed Mycobacterium tuberculosis. Control F344/N and LEW/N rats were maintained on either antalarmin or vehicle. RESULTS: Chronic blockade of CRH-R1 with systemic antalarmin significantly ameliorated AIA in LEW/N rats, reducing the severity of inflammation in peripheral joints, evidenced by clinical and histopathology scores, and weight loss associated with disease onset. Antalarmin neither induced nor exacerbated arthritis expression in F344/N or LEW/N rats, despite suppression of levels of adjuvant induced corticosterone, the major antiinflammatory glucocorticoid in rats. CONCLUSION: Systemic blockade of CRH-RI appeared to predominantly block peripheral proinflammatory effects of immune CRH, rather than the systemic glucocorticoid mediated antiinflammatory effects of hypothalamic CRH. Results indicate that chronic treatment with a CRH antagonist attenuates progressive inflammation induced degeneration of synovia, cartilage, and bone in arthritic joints, suggesting that antalarmin may have therapeutic potential in treatment of human autoimmune and inflammatory disorders.

CRHR1 Receptor binding and lipophilicity of pyrrolopyrimidines, potential nonpeptide corticotropin-releasing hormone type 1 receptor antagonists.

A series of compounds related to N-butyl-N-ethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amine (1, antalarmin) have been prepared and evaluated for their CRHR1 binding affinity as the initial step in the development of selective high affinity hydrophilic nonpeptide corticotropin-releasing hormone type 1 receptor (CRHR1) antagonists. Calculated log P (Clog P) values were used to evaluate the rank order of hydrophilicity for these analogues. Introducing oxygenated functionalities (delta-hydroxy or bis-beta-ethereal) into 1 gave more hydrophilic compounds, which had good affinity for the receptor. Introducing an amino group or shortening the alkyl side chain was detrimental to CRHR1 affinity. The alcohol 4-[ethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]butan-1-ol (3), bearing a terminal hydroxyl group on an N-alkyl side-chain, showed the highest CRHR1 binding affinity among these compounds (K(i)=0.68 nM), and is one of the highest affinity CRHR1 ligands known. Compounds 3-5, and 8, which are likely to be less lipophilic than 1, have high CRHR1 affinity and may be valuable probes to further study the CRH system.