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Questions and Answers
Mianserin combined with FGA (30mg/day) has extensive RCT evidence supporting its efficacy.
Mianserin combined with FGA (30mg/day) has extensive RCT evidence supporting its efficacy.
False
Minocycline 200mg/day may have anti-inflammatory and neuroprotective effects based on one open study and one RCT.
Minocycline 200mg/day may have anti-inflammatory and neuroprotective effects based on one open study and one RCT.
True
Mirtazapine 30mg/day combined with an antipsychotic has consistently positive results in RCTs.
Mirtazapine 30mg/day combined with an antipsychotic has consistently positive results in RCTs.
False
N-acetylcysteine 2g/day combined with an antipsychotic has been shown to provide benefits in both negative symptoms and rates of akathisia.
N-acetylcysteine 2g/day combined with an antipsychotic has been shown to provide benefits in both negative symptoms and rates of akathisia.
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Olanzapine 30-60mg/day is a typical antipsychotic and is associated with minor side effects.
Olanzapine 30-60mg/day is a typical antipsychotic and is associated with minor side effects.
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Omega 3 triglycerides have extensive data supporting their efficacy.
Omega 3 triglycerides have extensive data supporting their efficacy.
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Ondansetron 8mg/day combined with an antipsychotic has a conclusive effect on cognition.
Ondansetron 8mg/day combined with an antipsychotic has a conclusive effect on cognition.
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Paliperidone LAI has been shown to improve clinical outcomes in patients switched from clozapine.
Paliperidone LAI has been shown to improve clinical outcomes in patients switched from clozapine.
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Olanzapine combined with risperidone may benefit some patients after the sequential failure of each drug alone.
Olanzapine combined with risperidone may benefit some patients after the sequential failure of each drug alone.
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High dose Olanzapine is well-tolerated and does not lead to metabolic changes.
High dose Olanzapine is well-tolerated and does not lead to metabolic changes.
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Bexarotene 75mg/day is effective for treating positive symptoms in non-refractory patients.
Bexarotene 75mg/day is effective for treating positive symptoms in non-refractory patients.
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Blonanserin has been licensed worldwide as an atypical antipsychotic.
Blonanserin has been licensed worldwide as an atypical antipsychotic.
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Celecoxib + risperidone has been associated with decreased cardiovascular mortality.
Celecoxib + risperidone has been associated with decreased cardiovascular mortality.
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CBT should always be considered as a non-drug therapy for schizophrenia.
CBT should always be considered as a non-drug therapy for schizophrenia.
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Deep Brain Stimulation targeting the nucleus accumbens has shown effectiveness in all TRS patients in studies.
Deep Brain Stimulation targeting the nucleus accumbens has shown effectiveness in all TRS patients in studies.
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Donepezil, a glycine NMDA agonist, has shown positive results in one RCT.
Donepezil, a glycine NMDA agonist, has shown positive results in one RCT.
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Ginkgo biloba is often effective on its own without combining with any antipsychotic.
Ginkgo biloba is often effective on its own without combining with any antipsychotic.
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Estradiol has shown benefits in women of child-bearing age for positive symptoms of schizophrenia.
Estradiol has shown benefits in women of child-bearing age for positive symptoms of schizophrenia.
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Famotidine showed improvement in all symptom domains in a six-month study.
Famotidine showed improvement in all symptom domains in a six-month study.
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One RCT comparing standard with high dose lurasidone found it as effective for TRS patients when given up to 24 weeks.
One RCT comparing standard with high dose lurasidone found it as effective for TRS patients when given up to 24 weeks.
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There is very weak evidence supporting the use of NMDA receptor modulators as adjuncts in treating refractory schizophrenia.
There is very weak evidence supporting the use of NMDA receptor modulators as adjuncts in treating refractory schizophrenia.
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Polypharmacy involving non-clozapine antipsychotics has strong evidence of effectiveness in treating refractory schizophrenia.
Polypharmacy involving non-clozapine antipsychotics has strong evidence of effectiveness in treating refractory schizophrenia.
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Electroconvulsive therapy (ECT) has the best evidence as an adjunct treatment to clozapine compared to other physical treatments for refractory schizophrenia.
Electroconvulsive therapy (ECT) has the best evidence as an adjunct treatment to clozapine compared to other physical treatments for refractory schizophrenia.
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Monotherapy using non-clozapine antipsychotics such as aripiprazole has a strong evidence base for its efficacy.
Monotherapy using non-clozapine antipsychotics such as aripiprazole has a strong evidence base for its efficacy.
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Adjunctive antidepressants like mirtazapine and SSRIs show moderate benefits in treating cognitive symptoms in refractory schizophrenia.
Adjunctive antidepressants like mirtazapine and SSRIs show moderate benefits in treating cognitive symptoms in refractory schizophrenia.
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The combination of lamotrigine and antipsychotics is supported by strong evidence for treating refractory schizophrenia.
The combination of lamotrigine and antipsychotics is supported by strong evidence for treating refractory schizophrenia.
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Anti-inflammatory agents as adjuncts to antipsychotics may have possible benefits in negative and cognitive symptoms, but the sample sizes in studies have been large.
Anti-inflammatory agents as adjuncts to antipsychotics may have possible benefits in negative and cognitive symptoms, but the sample sizes in studies have been large.
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The use of CBT in treating refractory schizophrenia has conflicting findings with only small effects observed.
The use of CBT in treating refractory schizophrenia has conflicting findings with only small effects observed.
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Allopurinol, used at doses of 300-600mg/day, has three positive randomized controlled trials (RCTs) supporting its efficacy when combined with an antipsychotic.
Allopurinol, used at doses of 300-600mg/day, has three positive randomized controlled trials (RCTs) supporting its efficacy when combined with an antipsychotic.
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Amisulpride has multiple large-scale randomized controlled studies supporting its efficacy at doses up to 1200mg/day.
Amisulpride has multiple large-scale randomized controlled studies supporting its efficacy at doses up to 1200mg/day.
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Antipsychotic polypharmacy has robust randomized controlled trial data supporting its effectiveness.
Antipsychotic polypharmacy has robust randomized controlled trial data supporting its effectiveness.
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Aripiprazole has shown a moderate effect in patients resistant to risperidone or olanzapine in a single randomized controlled study at doses of 15-30mg/day.
Aripiprazole has shown a moderate effect in patients resistant to risperidone or olanzapine in a single randomized controlled study at doses of 15-30mg/day.
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Higher doses of Aripiprazole, even up to 120mg/day, have been utilized in studies.
Higher doses of Aripiprazole, even up to 120mg/day, have been utilized in studies.
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Asenapine's efficacy has primarily been supported by two case reports when used in combination with another antipsychotic.
Asenapine's efficacy has primarily been supported by two case reports when used in combination with another antipsychotic.
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The use of propentofylline paired with risperidone has been suggested to have activity against positive symptoms.
The use of propentofylline paired with risperidone has been suggested to have activity against positive symptoms.
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Quetiapine and amisulpride combination treatment resulted in high efficacy based on extensive clinical trials with numerous patients.
Quetiapine and amisulpride combination treatment resulted in high efficacy based on extensive clinical trials with numerous patients.
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Topiramate has been shown to induce weight loss in patients receiving antipsychotic treatment.
Topiramate has been shown to induce weight loss in patients receiving antipsychotic treatment.
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Clinical improvement with pimavanserin was observed only when combined with clozapine.
Clinical improvement with pimavanserin was observed only when combined with clozapine.
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Sertindole demonstrated clear and consistent effectiveness in all trials on patients with schizophrenia.
Sertindole demonstrated clear and consistent effectiveness in all trials on patients with schizophrenia.
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Raloxifene is a selective estrogen receptor modulator that may offer benefits without the long-term risks associated with estradiol.
Raloxifene is a selective estrogen receptor modulator that may offer benefits without the long-term risks associated with estradiol.
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Yokukansan, when used alone, showed significant efficacy in managing schizophrenia.
Yokukansan, when used alone, showed significant efficacy in managing schizophrenia.
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Risperidone LAI had similar plasma levels for the 50mg and 100mg doses as compared to a 4-6mg/day oral risperidone.
Risperidone LAI had similar plasma levels for the 50mg and 100mg doses as compared to a 4-6mg/day oral risperidone.
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Clozapine treatment should be delayed or withheld in cases where treatment resistance has been established.
Clozapine treatment should be delayed or withheld in cases where treatment resistance has been established.
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The practice of using successive antipsychotic medications instead of clozapine is supported by research.
The practice of using successive antipsychotic medications instead of clozapine is supported by research.
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Long-term data on efficacy and safety/tolerability are generally available for antipsychotic medications.
Long-term data on efficacy and safety/tolerability are generally available for antipsychotic medications.
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Olanzapine is rarely used as antipsychotic monotherapy in practice.
Olanzapine is rarely used as antipsychotic monotherapy in practice.
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The risk-benefit balance of combined antipsychotic medication regimens is well established.
The risk-benefit balance of combined antipsychotic medication regimens is well established.
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Depot/LAI antipsychotic preparations are not an option for treating treatment-resistant schizophrenia.
Depot/LAI antipsychotic preparations are not an option for treating treatment-resistant schizophrenia.
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Minocycline and ondansetron have high toxicity and poor tolerability.
Minocycline and ondansetron have high toxicity and poor tolerability.
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All treatments listed in the text are well-established and widely used for treating schizophrenia.
All treatments listed in the text are well-established and widely used for treating schizophrenia.
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Study Notes
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.
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Description
This quiz covers alternative treatments to clozapine, including allopurinol, amisulpride, antipsychotic polypharmacy, and aripiprazole. Learn about their effects and efficacy in treating psychiatric disorders.
