Disturbance of Plasma Cytokine Parameters in Clozapine-Resistant Treatment-Refractory Schizophrenia (CTRS) and Their Association With Combination Therapy

Schizophrenia is one of the most serious mental illnesses worldwide that affects approximately 1% of the worldwide population and result in a heavy economic burden to affected family. Antipsychotics are the main stay of treatment of schizophrenia, however, there are still approximately 1/3 schizophrenia patients who does not responded to the antipsychotic agents, and these patients easily develop into treatment-refractory schizophrenia (TRS). Clozapine is the only evidence based effective medication for treatment-refractory schizophrenia (TRS). In spite of its prominent efficacy, approximately 1/3-2/1 treatment-refractory schizophrenia (TRS) treated with clozapine still present with significant residual psychotic symptoms and negative symptoms. As such, over time, clinicians struggled to find strategies to improve outcome by augmenting the concomitant psychiatric treatments, including not only combining antipsychotics but also combining a mood stabilizer or electroconvulsive therapy (ECT). Clozapine is an antipsychotic drug with multi receptor blocking effect and has a low affinity for dopamine D2. Studies of traditional antipsychotics have suggested that maximal efficacy occurs with dopamine D2 occupancy of 70% or more, while clozapine's dopamine D2 occupancy levels less than 60%. Amisulpride has a highly selective blocking effect on dopamine D2 and dopamine D3 receptors and has no affinity for any other known receptors. Its unique dopamine receptor blocking effect may selectively enhances the limited dopamine D2 blocking effect of clozapine, making it possible to be a suitable and effective drug for combination with clozapine. A number of promising studies that have augmented clozapine with amisulpride, have shown psychiatric symptoms improvement in TRS versus those on clozapine alone. Both electroconvulsive therapy (ECT) and antiepileptic drugs, such as sodium valproate, shares anticonvulsant properties and anticonvulsant effect relate to clinical efficacy. In 1983, Sackeim et al. pointed out that electroconvulsive therapy (ECT)-induced cortical gamma-aminobutyric-acid (GABA) depletion may be the reason for its anticonvulsant action. In addition, the effect of electroconvulsive therapy (ECT) on the gamma-aminobutyric-acid (GABA) system was confirmed by several studies. Interestingly, it has been reported that the therapeutic effect of sodium valproate combined with antipsychotics is closely related to gamma-aminobutyric-acid (GABA) system. Growing evidence suggests that the immune, endocrine, and nervous systems interact with each other through cytokines, hormones, and neurotransmitters. The activation of the immune system may be involved in the neuropathological changes occurring in the central nervous system. Among several components of immune pathogenesis, aberrant cytokine signaling is considered as one of the key contributors. Many cytokines have been speculated to be involved in the pathological process of schizophrenia. IL-2 acts as a growth factor for T cells, NK cells and B cells, abnormalities of IL-2 serum levels or its production were found in acute schizophrenia cases. IL-6 is an inflammatory cytokine, which plays significant role in neurobiological functions like neuronal differentiation and survival, synaptic transmission and brain morphometry. The abnormal expression of IL-6 can be found in both first-episode and chronic schizophrenia. TNF-α is one of the most important pro-inflammatory cytokines, which expressed mainly by macrophages. Previous studies have found that the expression of TNF-α is abnormal in patients with schizophrenia. The primary objective of this study was to compare the efficacy and safety between sodium valproate, amisulpride and MECT combination therapy in clozapine-treated refractory schizophrenia during a 12 weeks period. In addition, the effect of combined therapy on plasma cytokines (IL-2, IL-6 and TNF-α) will be evaluated.