Table 2. Overview of treatment strategies for TRS.

We review the advantages of disadvantages of various treatment strategies for treatment resistant schizophrenia (TRS). We give general overviews of medications, brain stimulation procedures, and psychotherapeutic methods, and then discuss specific examples in these categories. ECT = electroconvulsive therapy; rTMS = repetitive transcranial magnetic stimulation; AH = auditory hallucinations; DBS = deep brain stimulation; CBT = cognitive-behavioral therapy; CR = cognitive remediation.

	ADVANTAGES	DISADVANTAGES
Medications	General: - Easy clinical implementation - Non-invasive Clozapine: - Up to 60% of TRS patients respond to clozapine - Most efficacious antipsychotic - Reduces suicide and violence Clozapine augmentation with medications: - Relatively easy (especially compared to non-pharmacologic al modalities)	General: - Approximately 30% of TRS patients do not respond to any medication - Limited by non-compliance Clozapine: - Well-known adverse effects (e.g. agranulocytosis) - Requires enrollment in national registry and regular blood monitoring Clozapine augmentation with medications: - Minimal benefit for TRS - Greater risk of adverse effects from polypharmacy
Brain Stimulation	General: - Novel treatments with the potential to address mechanisms unaffected by medications - Can augment medications ECT: - Extensive use for mood disorders - Evidence of efficacy for positive symptoms in TRS - Evidence of synergistic effects with clozapine - Non-invasive procedure rTMS: - Evidence of efficacy for persistent AH - Potentially treats negative symptoms (currently few other treatment options) - Non-invasive procedure DBS: - Only intracranial intervention available, can directly target specific brain areas	General: - Procedural, so can be invasive and/or require anesthesia - Not as established as medications, requires more study ECT: - Adverse effects (e.g. memory impairment) - Require multiple treatments and possible long-term maintenance - Unclear benefit for domains other than positive symptoms - Requires anesthesia rTMS: - Require multiple treatments and possible longterm maintenance - Long-term side effects unknown DBS: - Invasive surgical procedure - Risk of hardware malfunction - Relatively new in schizophrenia
Psychotherapy	General: - Can augment medications - Efficacy in reducing symptom burden - Non-invasive CBT: - Possible efficacy for overall impairment and positive symptoms (e.g. AH) in TRS CR: - Possible efficacy for cognitive deficits in TRS	General: - Time-intensive - Requires baseline capacity to participate/engag e - Very few studies specifically assessing TRS CBT: - Requires trained staff CR: - Treatment techniques and validated measurements still in development