Because treatment-resistant schizophrenia (TRS) is notoriously challenging to treat — as many as 45% of patients are refractory to treatment — clinicians are continually searching for therapeutic augmentation.1 It is incumbent upon clinicians to update their knowledge on the advances in therapeutics while maintaining a discerning attitude toward clinical trial data, especially meta-analyses.1

The Challenge of Evaluating Schizophrenia Augmentation Therapy

Schizophrenia is a heterogeneous disorder with variable responses to treatment so it is difficult to devise trials that replicate clinical scenarios.2 “It is necessary to dynamically change the curriculum vitae of medical students, young doctors, and young psychiatrists paralleling the increasing amount of new knowledge,” said psychiatrist Eva Češková, MD, PhD, from the Faculty Hospital Brno in Bohunice, Czech Republic. “If medical professionals have basic information about genetics, pharmacogenetics, and pharmacodynamics, they will be better able to determine the quality of research.”

How to Evaluate Augmentation Studies

In assessing the effectiveness of statins as add-on therapy for schizophrenia, psychiatrist Chittaranjan Andrade, MD, from the National Institute of Mental Health and Neurosciences in Bangalore, India, advised, “Clinicians should certainly consider the use of statins for patients with schizophrenia. However, the purpose should be the treatment of the metabolic disturbances associated with the illness and its treatment. Statins should not be prescribed as antipsychotic augmentation agents for the attenuation of positive, negative, or other symptoms of schizophrenia because the evidence, presently, does not support their use for this indication.”

Andrade cited examples of 2 statin augmentation meta-analyses for schizophrenia. Both analyses were flawed because the studies included varying stages of illness (eg, the selection of chronically ill patients with mostly negative symptoms) and the pooling of end point and change scores.1 Combining these scores is statistically erroneous and clinically meaningless.1

Moreover, both meta-analyses had few studies: one had 5 randomized controlled trials (RCTs) and the other included 6 RCTs.1 Andrade also cautioned about using individual studies that are flawed to begin with, especially those that start with data collection errors.1

“It is difficult for clinicians who are not in academia to be sufficiently well versed in matters related to statistics and research methodology to be able to fully understand the strengths and limitations of unapproved treatment approaches,” said Dr Andrade. “Clinicians should therefore adhere to treatment guidelines issued by competent organizations, conservative though these guidelines may be.”

Treatment-Resistant Schizophrenia Is Challenging to Define

Compounding matters for patients with treatment-refractory schizophrenia is the definition of “response” to therapy, because while patients may improve according to some measures they may still exhibit residual symptoms such as mild delusions or hallucinations.3 In practice, when clinicians record symptoms of patients with schizophrenia, they seldom do so with the standardized rating scales.3

For research purposes, a consensus group proposed that the term “treatment-resistant schizophrenia” should refer to:3

  • Moderate severity of functional impairments measured by a standardized rating scale
  • Six or more weeks on a different antipsychotic agent
  • Two or more previous adequate treatment episodes, and
  • Adherence to medication for at least 80% of the time measured by plasma levels

To further explain the lack of response to treatment, researchers suggested that the prevailing symptom domain be labeled treatment-refractory schizophrenia (TRS)-positive symptom domain and ultra-TRS after clozapine failure.3

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“Research on TRS and other difficult-to-treat psychiatric illnesses have been hampered by the lack of uniform diagnostic criteria,” explained Justin Faden, DO, assistant professor of psychiatry and behavioral science at the Lewis Katz School of Medicine at Temple University in Philadelphia, Pennsylvania. “When reviewing the quality of research on augmentation strategies for TRS, or other refractory conditions, see what diagnostic criteria is being used, and how applicable it is to real-world patients. Having uniform criteria will allow for higher quality evidence and more useful and relevant meta-analyses, which struggle with heterogeneous patient populations. When scales are utilized, look for measures of functional impairment or quality of life improvement.”

The Evidence Base for Clozapine-Resistant Schizophrenia (CRS)

To better define treatment-refractory schizophrenia, psychiatrist Dan J Siskind, MBBS, MPH, PhD, from the University of Queensland in Brisbane, Queensland, Australia, and colleagues limited their global meta-analysis of 46 studies to patients who did not respond to clozapine, an antipsychotic that has shown promise in improving positive symptoms and reducing hospitalization in patients who have failed other modalities.4,5

In one of the first meta-analyses to incorporate both pharmacologic and nonpharmacologic modalities for CRS, the review included 2223 participants and 25 interventions, including antipsychotics, antidepressants, and mood stabilizers, as well as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and cognitive behavioral therapy (CBT).4

The comprehensive meta-analysis found that of the add-on pharmacologic agents, aripiprazole, fluoxetine, and sodium valproate were the most effective in improving total psychosis symptoms, whereas memantine was most effective for negative symptoms.4 Of the nonpharmacologic interventions, ECT was the most efficacious.4

“Although meta-analysis of RCT evidence is often considered the highest level of evidence, RCTs may not always reflect ‘real-world’ treatment situations,” said Dr Siskind. “Meta-analyses of RCTs are only as good as the included RCTs. Naturalistic before and after studies can be useful.  For example, a meta-analysis of the impact of clozapine for hospitalizations from naturalistic studies found that starting clozapine can lead to a 26% reduction in hospitalizations, and a reduction in psychiatric bed days of over 34 days.”5

Summary & Clinical Applicability

As much as one-third of patients with schizophrenia are refractory to treatment. Thus, clinicians should be discerning when evaluating meta-analyses of schizophrenia add-on therapies such as statins and antidepressants.

Limitations & Disclosures



  1. Andrade C. The use of statins for antipsychotic augmentation in schizophrenia: examination of meta-analyses with flawed methods and conclusions.J Clin Psychiatry. 2018;79(5). doi:10.4088/JCP.18f12562
  2. Češková E, Silhan P. Novel treatment options in depression and psychosis.Neuropsychiatr Dis Treat. 2018;14:741-747. doi:10.2147/NDT.S157475
  3. Faden J, Citrome L. Resistance is not futile: treatment-refractory schizophrenia–overview, evaluation and treatment. Expert Opin Pharmacother. 2018;1-14. doi:10.1080/14656566.2018.1543409
  4. Siskind DJ , Lee M , Ravindran A, et al. Augmentation strategies for clozapine refractory schizophrenia: a systematic review and meta-analysis.Aust N Z J Psychiatry. 2018;52(8):751-767. doi:10.1177/0004867418772351
  5. Land R, Siskind D, McArdle P, Kisely S, Winckel K, Hollingworth SA. The impact of clozapine on hospital use: a systematic review and meta-analysis.Acta Psychiatr Scand. 2017;135(4):296-309. doi:10.1111/acps.12700