Alternative Treatments to Clozapine

Alternative Treatments to Clozapine

• Allopurinol 300-600mg/day: increases adenosinergic transmission, may reduce dopamine effects, supported by three positive RCTs.
• Amisulpride (up to 1200mg/day): single small open study.
• Antipsychotic polypharmacy: various antipsychotics in combination, data limited, mainly in case reports and open studies.
• Aripiprazole (15-30mg/day): single randomized controlled study, moderate effect in patients resistant to risperidone or olanzapine.
• Asenapine (+ antipsychotic): two case reports.
• Pimavanserin (+ antipsychotics): clinical improvement in 10 patients, six of whom failed to respond to clozapine.
• Propentofylline + risperidone (900mg + 6mg/day): one RCT suggests some activity against positive symptoms.
• Quetiapine: very limited evidence, clinical experience not encouraging, high doses (>1200mg/day) used but no more effective.
• Quetiapine + amisulpride: single naturalistic observation of 19 patients, suggested useful benefit.
• Quetiapine + haloperidol: two case reports.
• Raloxifene 60-120mg/day (+ antipsychotic): selective oestrogen receptor modulator, may offer benefits of estradiol without long-term risks, one case report in postmenopausal treatment-resistant schizophrenia.
• Riluzole 100mg/day + risperidone up to 6mg/day: glutamate modulating agent, one RCT demonstrated improvement in negative symptoms.
• Risperidone 4-8mg/day: doubtful efficacy in true treatment-refractory schizophrenia, but some supporting evidence.
• Sarcosine (2g/day) (+ antipsychotic): enhances glycine action, supported by two RCTs.
• Sertindole (12-24mg/day): one large RCT suggested good effect and equivalence to risperidone, another RCT showed no effect at all when added to clozapine.

Table 1.37 (Continued)

• Mianserin + FGA 30mg/day: 5HT antagonist, one small positive RCT.
• Minocycline 200mg/day (+ antipsychotic): may be anti-inflammatory and neuroprotective, one open study and one RCT suggest good effect on negative and cognitive symptoms.
• Mirtazapine 30mg/day (+ antipsychotic): 5HT antagonist, two RCTs, one negative and one positive, effect seems to be mainly on positive symptoms.
• N acetylcysteine 2g/day (+ antipsychotic): one RCT suggests small benefits in negative symptoms and rates of akathisia, another RCT showed benefits in chronic schizophrenia.

Treatments for Schizophrenia

• Bexarotene 75mg/day (+ antipsychotic): retinoid receptor agonist, one RCT suggests worthwhile effect on positive symptoms.
• Blonanserin (+ antipsychotic): atypical antipsychotic licensed in Japan and Korea, one case series found it to be effective and well-tolerated.
• CBT: non-drug therapies should always be considered.
• Celecoxib + risperidone (400mg + 6mg/day): COX-2 inhibitors modulate immune response and may prevent glutamate-related cell death, one RCT showed useful activity in all main symptom domains.
• Deep Brain Stimulation (DBS): effectiveness of nucleus accumbens and subgenual anterior cingulate cortex targeted DBS demonstrated in 4 of 7 patients with TRS, three RCTs, one negative and two positive, suggesting a small effect on cognitive and negative symptoms.

Refractory Schizophrenia — Alternatives to Clozapine

• Monotherapy using non-clozapine antipsychotics in standard or high doses: evidence of efficacy for any antipsychotic other than clozapine in refractory schizophrenia is sparse.
• Non-clozapine antipsychotic polypharmacy: polypharmacy is common in clinical practice, evidence from controlled studies limited, but open studies and real-world data suggest some effectiveness.
• Anti-inflammatory agents as adjuncts to antipsychotics: possible benefits in negative and cognitive symptoms, but sample sizes have been small.
• NMDA receptor modulators as adjuncts: rarely used in clinical practice, may have some benefit in negative symptoms.
• Physical treatments: ECT, rTMS, tDCS, DBS, best evidence for ECT as adjunct to clozapine.
• Adjunctive antidepressants: limited data available, suggests small benefits in negative and cognitive symptoms.
• Adjunctive antiseizure medications: data difficult to interpret, including clozapine and non-clozapine antipsychotics, modest benefits at best.
• Psychological therapies: conflicting findings, effects small.

Treatment of Refractory Schizophrenia

• Clozapine has the strongest evidence for efficacy in treating schizophrenia that has proven refractory to standard antipsychotic medication.
• Clozapine treatment should not be delayed or withheld when treatment resistance has been established.

Alternative Treatment Options

• In cases where clozapine cannot be used, other drugs or drug combinations may be tried, but outcomes are often disappointing.
• Long-term data on efficacy and safety/tolerability are generally lacking.

Antipsychotic Medication Regimens

• There is no distinction between treatment regimens, but it is wise to use single drugs before trying multiple drug options.
• Olanzapine is often used as antipsychotic monotherapy, usually in dosages above the licensed range.

Combination Therapy

• Adding a second antipsychotic (e.g., amisulpride) may be a possible next step, but the risk-benefit balance of combined antipsychotic medication regimens remains unclear.

Unconventional Agents

• Minocycline and ondansetron have low toxicity and good tolerability, making them potential treatment options.

Depot/LAI Antipsychotic Preparations

• Depot/LAI antipsychotic preparations are an option when the avoidance of covert non-adherence is a clinical priority.

Experimental Treatments

• Treatments like glycine, D-serine, and sarcosine are somewhat experimental and difficult to obtain.
• Particular care should be taken when prescribing off-label and informing patients of potential adverse effects.

Future Directions

• Non-clozapine treatment of refractory schizophrenia is an active area of research.
• Glutamatergic drugs and 5HT2A inverse agonists may hold promise for future treatment options.