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Completed

NCT Number: NCT03652974

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

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).

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Key information

Conditions

Schizophrenia Mental Disorders Schizophrenia Spectrum and Other Psychotic Disorders

Age range

18 year–60 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Shanghai Mental Health Center

Shanghai, Shanghai Municipality, 200030, China

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • The diagnosis of schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)
  • 18～60 years old
  • Clozapine resistance was defined as used at least two antipsychotics with different chemical structures with appropriate dosages for a sufficient duration, and recently have received stable dose of clozapine 400 mg or more per day for at least 6 months.
  • Signed an informed consent

Exclusion criteria

  • Patients to be diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) for substance abused, development delayed
  • Suffering from serious physical disease and can not accept the treatment
  • Allergic to sodium valproate, amisulpride, propofol, succinylcholine or atropine
  • Participated in any clinical subject within 30 days
  • Pregnancy or lactation
  • Inability to sign informed consent because of capacity due due to severe mental illness, significant psychomotor agitation or slowness test completion

Treatment and study plan

sodium valproate with Clozapine

Drug

sodium valproate may be used as a synergistic agent of clozapine in the treatment of treatment-refractory schizophrenia

Other names: Valproate

modified electroconvulsive therapy(MECT) with Clozapine

Device

modified electroconvulsive therapy(MECT) may be used as a synergistic agent of clozapine in the treatment of treatment-refractory schizophrenia

amisulpride with Clozapine

Drug

amisulpride may be used as a synergistic agent of clozapine in the treatment of treatment-refractory schizophrenia

placebo with Clozapine

Drug

placebo may be used as a synergistic agent of clozapine in the treatment of treatment-refractory schizophrenia

Primary outcomes

  1. Positive and Negative Syndrome Scale (PANSS)

    Time frame: the baseline

    The battery of Positive and Negative Syndrome Scale (PANSS) test will be administered in a 30-minute sessions to evaluate the psychiatric symptoms.

  2. Positive and Negative Syndrome Scale (PANSS)

    Time frame: the end of the six week

    The battery of Positive and Negative Syndrome Scale (PANSS) test will be administered in a 30-minute sessions to evaluate the psychiatric symptoms.

  3. Positive and Negative Syndrome Scale (PANSS)

    Time frame: the end of the twelve week

    The battery of Positive and Negative Syndrome Scale (PANSS) test will be administered in a 30-minute sessions to evaluate the psychiatric symptoms.

  4. Scale for the Assessment of Negative Symptoms (SANS)

    Time frame: the baseline

    The Scale for the Assessment of Negative Symptoms (SANS) was applied to assess negative symptoms.

  5. Scale for the Assessment of Negative Symptoms (SANS)

    Time frame: the end of the six week

    The Scale for the Assessment of Negative Symptoms (SANS) was applied to assess negative symptoms.

  6. Scale for the Assessment of Negative Symptoms (SANS)

    Time frame: the end of the twelve week

    The Scale for the Assessment of Negative Symptoms (SANS) was applied to assess negative symptoms.

  7. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

    Time frame: the baseline

    The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to evaluate the cognitive performance.

  8. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

    Time frame: the end of the six week

    The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to evaluate the cognitive performance.

  9. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

    Time frame: the end of the twelve week

    The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to evaluate the cognitive performance.

  10. Clinical Global Impression (CGI)

    Time frame: the baseline

    The Clinical Global Impression (CGI) including severity scale (CGI-S), improvement scale (CGI-I), and efficacy index (CGI-E) was used to evaluate the severity of symptoms and treatment response and treatment effect, respectively.

  11. Clinical Global Impression (CGI)

    Time frame: the end of the six week

    The Clinical Global Impression (CGI) including severity scale (CGI-S), improvement scale (CGI-I), and efficacy index (CGI-E) was used to evaluate the severity of symptoms and treatment response and treatment effect, respectively.

  12. Clinical Global Impression (CGI)

    Time frame: the end of the twelve week

    The Clinical Global Impression (CGI) including severity scale (CGI-S), improvement scale (CGI-I), and efficacy index (CGI-E) was used to evaluate the severity of symptoms and treatment response and treatment effect, respectively.

  13. Treatment Emergent Symptom Scale (TESS)

    Time frame: the baseline

    The Treatment Emergent Symptom Scale (TESS) was used to assess the severity of treatment adverse events.

  14. Treatment Emergent Symptom Scale (TESS)

    Time frame: the end of the six week

    The Treatment Emergent Symptom Scale (TESS) was used to assess the severity of treatment adverse events.

  15. Treatment Emergent Symptom Scale (TESS)

    Time frame: the end of the twelve week

    The Treatment Emergent Symptom Scale (TESS) was used to assess the severity of treatment adverse events.

  16. plasma cytokines IL-2, IL-6 and TNF-α

    Time frame: the baseline

    The plasma cytokines IL-2, IL-6 and TNF-α would be measured using ELISA kits (R & D Systems, Mississauga, Ontario, CANADA).

  17. plasma cytokines IL-2, IL-6 and TNF-α

    Time frame: the end of the twelve week

    The plasma cytokines IL-2, IL-6 and TNF-α would be measured using ELISA kits (R & D Systems, Mississauga, Ontario, CANADA).

Sponsors and collaborators

Lead sponsor

Shanghai Mental Health Center

Other

Collaborators

  • Shanghai Pudong New Area Mental Health Center, School of Medicine, Tongji University
  • The Affiliated Brain Hospital of Guangzhou Medical University

Registry information

Important dates

Study start
2018
Primary completion
2021
Study completion
2021
First posted
Aug 31, 2018
Registry last updated
Sep 6, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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