Current Treatment Options in Psychiatry

, Volume 6, Issue 1, pp 32–63 | Cite as

Treatment of Clozapine Nonresponders

  • Sandeep GroverEmail author
  • Swapnajeet Sahoo
Schizophrenia and Other Psychotic Disorders (J Csernansky, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Schizophrenia and Other Psychotic Disorders


Purpose of review

Significant proportions of patients with treatment-resistant schizophrenia (TRS) do not respond to clozapine and are known as clozapine nonresponders or ultra-resistant schizophrenia. They are among the most difficult patients to treat. This article attempts to review the available evidence for management of patients with schizophrenia, who do not respond adequately to clozapine and require augmentation of clozapine with another treatment strategy.

Recent findings

Many treatment strategies have been evaluated for management of this group of patients. Commonly used pharmacological augmentation strategies which have been evaluated include addition of a second antipsychotic, mood stabilizer, and antidepressant. Other pharmacological agents such as memantine, donepezil, amino acids, omega-3 fatty acids etc. have also been tried. Among the somatic treatments, electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS) have also been evaluated. Non-pharmacological strategies such as cognitive behavior therapy and occupational therapy have also been evaluated clozapine non-response cases. However, at the present, the data is limited to small sample size studies and is not sufficient to make any specific recommendation.


Among the various strategies evaluated, ECT is possibly the most effective augmentation strategy in patients not responding or partially responding to clozapine. Among the various pharmacological agents, if the target is positive symptoms, then one of the second-generation antipsychotic like amisulpride or aripiprazole may be considered. If the target is negative symptoms, then amisulpride, mirtazapine, lamotrigine, fluvoxamine, and memantine may be considered. However, it is important to remember that use of combination is associated with more side effects and the patients must be closely monitored. If the patients do not respond to combination, then the same must be abandoned after 3–6 months.


Clozapine Non- response Augmentation strategy 


Compliance with Ethical Standards

Conflict of Interest

Dr. Sandeep Grover declares that he has no conflict of interest.

Dr. Swapnajeet Sahoo declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of PsychiatryPGIMERChandigarhIndia

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