Disturbance of Plasma Cytokine Parameters in Clozapine-Resistant Treatment-Refractory Schizophrenia (CTRS) and Their Association With Combination Therapy
Condition: Schizophrenia
MeSH terms: Schizophrenia; Schizophrenia, Treatment-Resistant
Study type: Interventional
Phase: Phase 4

Summary: 
      In this study, investigators designed a double-blind randomized trial to compare the efficacy
      and safety between sodium valproate, amisulpride and MECT combination therapy in
      clozapine-treated refractory schizophrenia (CTRS).
    

Detailed description: 
      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.
    

Intervention name(s): sodium valproate with Clozapine; modified electroconvulsive therapy(MECT) with Clozapine; amisulpride with Clozapine; placebo with Clozapine
Intervention type(s): Drug; Device; Drug; Drug
Intervention description(s): sodium valproate may be used as a synergistic agent of clozapine in the treatment of treatment-refractory schizophrenia; modified electroconvulsive therapy(MECT) may be used as a synergistic agent of clozapine in the treatment of treatment-refractory schizophrenia; amisulpride may be used as a synergistic agent of clozapine in the treatment of treatment-refractory schizophrenia; placebo may be used as a synergistic agent of clozapine in the treatment of treatment-refractory schizophrenia
Other intervention name(s): Valproate
Intervention MeSH terms: Valproic Acid; Clozapine; Amisulpride
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Drug: amisulpride, sodium valproate , placebo and Clozapine amisulpride, sodium valproate and placebo may be used as a synergistic agent of clozapine in the treatment of treatment-resistant schizophrenia Other Name: Valproate Device: modified electroconvulsive therapy(MECT) with Clozapine modified electroconvulsive therapy(MECT) may be used as a synergistic agent of clozapine in the treatment of treatment-resistant schizophrenia Device: Modified electroconvulsive therapy(MECT) with Clozapine
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Schizophrenia， clozapine， amisulpride, valproate， ECT, cytokine