Japanese Society of Neuropsychopharmacology: “Guideline for Pharmacological Therapy of Schizophrenia”

Japanese Society of Neuropsychopharmacol… · 2021 · Japan

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Authors: Japanese Society of Neuropsychopharmacology
Title: Japanese Society of Neuropsychopharmacology: “Guideline for Pharmacological Therapy of Schizophrenia”
Journal: Neuropsychopharmacology Reports, 2021
DOI: 10.1002/npr2.12193
Licence: CC BY 4.0
Changes: Verbatim excerpts; formatting adapted

Full text retrieved 2026-10-27 from Europe PMC · PMC8411321

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Recommendations

Verbatim, with grade of recommendation or strength of consensus where given.

Recommendation

Aripiprazole has been reported to be effective at 9.9‐20.0 mg/d D Metabolic side effects have been reported with long‐term administration D.
Olanzapine has been reported to be effective at 8.7‐17.0 mg/d C. Almost all trials reported weight gain A.
Paliperidone has been reported to be effective at 6.4 mg/d but dyslipidemia have also been reported D.
Quetiapine has been shown to be effective at 311.4‐506 mg/d C. Treatment discontinuation rates tended to be higher than with other antipsychotics in long‐term administration trials B.
Risperidone had similar efficacy at 2 and 4 mg/d but a RCT reported that motor function was better at 2 mg/d C.
Haloperidol had similar efficacy at 2 and 8 mg/d but a RCT reported that EPS and hyperprolactinemia were lower at 2 mg/d C.
Aripiprazole has both high efficacy A and tolerability A at over10 mg/d.
Blonanserin is effective at either 2.5, 5, or 10 mg/d B.
Haloperidol is effective at over 10 mg/d A or over 4 mg/d B but the incidence of EPS is high at either dose A.
Olanzapine is effective at over 10 mg/d C but caution is required because of potential weight gain A.
Quetiapine is effective at over 250 mg/d B and may be effective even at over 150 mg/d C. Certainity of evidence for efficacy is weak to moderate, but tolerability is high A.
Risperidone is effective at over 2 mg/d A but increases in prolactin levels A, and drug‐induced Parkinsonism B are common. Caution is required because of side effects.
Zotepine is effective at over 150 mg/d C.
Clozapine with a concomitant use of ECT may have transient effects but is useful 2C.
Clozapine with a concomitant use of lamotrigine is potentially useful 2D.
Clozapine with a concomitant use of other mood stabilizers, antiepileptic drugs, antidepressants, and BZ drugs has not been shown to be useful, and it is suggested that these concomitant therapies be avoided in attempts to improve psychiatric symptoms 2D. The concomitant use of clozapine with valproic acid at the early stages of clozapine introduction is not recommended, due to the possible increase in myocarditis risk 1C.
Weak augmentation effects can be expected from clozapine with a concomitant use of antipsychotics, but clozapine monotherapy is stipulated in Japan as a general rule, and thus no recommendations are made (no recommendation C).
Administration of aripiprazole, olanzapine, and risperidone is desirable 2D.
Olanzapine is recommended 1D while haloperidol monotherapy is not desirable 2C. Despite the evidence for the combination of haloperidol+promethazine, no recommendation is made (promethazine injections are not indicated). Midazolam has also no indications (no recommendation for either C).
Haloperidol use is desirable 2D. There is some evidence for flunitrazepam but no recommendation is made for injections of flunitrazepam, which is not indicated (no recommendation) D.
Investigating options for the introduction of ECT is desirable when there is no response to pharmacotherapy 2D.
Searching for organic factors and improving general conditions are recommended before intervention 1D.
Considering the possibility of catatonia being the initial symptom of antipsychotic‐induced neuroleptic malignant syndrome, as well as suspending antipsychotics and prioritizing the treatment of neuroleptic malignant syndrome are recommended when the disease is suspected 1D.
It is desirable to pay sufficient attention to changes in the general condition and conduct pharmacological therapy according to normal schizophrenia treatment since there is not sufficient evidence regarding the efficacy and adverse events of pharmacological therapy limited to catatonia in schizophrenia 2D.
It is desirable to introduce ECT since there is established evidence of its effectiveness 2D.
There are various causes that may induce depressive symptoms in schizophrenia. It is recommended that they are distinguished by considering the symptoms of the illness itself, psychological reactions, and drug‐induced symptoms, and to take measures according to the cause 1D.
It is desirable to reduce the dose of antipsychotics when they are suspected of causing depression 2D.
With regard to switching antipsychotics, switching to SGAs is recommended when taking haloperidol 1C.
It is desirable not to use antidepressants or lithium concomitantly due to inconsistent results and the possibility of side effects occurring due to drug interactions 2D.
It is desirable not to conduct ECT since it has not shown any antidepressive effects 2D.
Antipsychotics improve cognitive impairment but the magnitude of these effects is small A.
SGAs have a slightly higher improvement effect than FGAs B.
There are no differences in improvement effects for cognitive function between drugs B.
Concomitant use of anticholinergic drugs and BZ drugs has an adverse effect on cognitive function D.
No improvement effects in cognitive function can be seen with cholinesterase inhibitor, mirtazapine, and mianserin addition therapy C.
It is recommended to use SGAs alone in appropriate doses and minimize concomitant use of anticholinergic drugs or BZ sedatives to improve cognitive impairment 1A.

Treatment after the onset of EPS

① Switching to SGAs which are less likely to cause Parkinsonism is recommended when Parkinsonism has occurred with FGAs which are likely to induce EPS 1A. Switching to clozapine, quetiapine, or olanzapine is desirable when the same side effects occur even when using SGAs 2D.
② Upon careful assessment of psychiatric symptoms, reducing the dose of orally administered antipsychotics is recommended if possible 1D.
③ Concomitant use of anticholinergic drugs (biperiden and trihexyphenidyl) or antiparkinsonian drugs (amantadine) is desirable when ① or ② cannot be selected or when antipsychotic drug adjustments alone are not effective 2D.
Oral anticholinergic drugs (biperiden and trihexyphenidyl), antihistamines (promethazine), or IM anticholinergic drug injections are desirable 2D.
Switching to aripiprazole, olanzapine, or quetiapine is desirable when acute dystonia is caused by high‐titer FGAs 2D.
One meta‐analysis compared high and low doses of antipsychotics for acute dystonia and showed that the onset risk was low in the low‐dose group D. Reduced doses of antipsychotics are desirable as an option 2D.
Active interventions such as pharmacotherapy, psychotherapy, and environmental adjustments are recommended when there is a high degree of urgency accompanied by severe anxiety and frustration, and where risks of suicidal ideations, suicide attempts, or other harm are expected 1D.
Reduced doses of the orally administered antipsychotic are recommended upon sufficient discussion with the patient when akathisia symptoms are mild 1D.
Switching to SGAs is recommended when high‐titer/high‐dose FGAs are prescribed 1C. Furthermore, using medium‐titer or low‐titer FGAs is desirable when switching to SGAs is not possible 2D.
The concomitant use of anticholinergic drugs, beta‐blockers (propranolol), clonazepam, mianserin, mirtazapine, trazodone, cyproheptadine, and vitamin B6 is not desirable 2D.
Switching to clozapine, olanzapine, and quetiapine after the onset of TD may reduce side effects D and it is desirable to switch to these drugs 2D.
Small‐scale RCT results showed that reduced doses of anticholinergic drugs decreased the severity of TD, so reducing doses during concomitant use of anticholinergic drugs is desirable 2D.
There is no established treatment method but switching to clozapine is desirable when selecting antipsychotics 2D.

Prevention of EPS

Prevention of drug‐induced Parkinsonism
Selecting SGAs is recommended over FGAs 1A.
Selecting one SGA among clozapine, quetiapine, or olanzapine is desirable 2D.
Selecting SGAs is recommended over FGAs 1C.
Anticholinergic drugs (biperiden and trihexyphenidyl) are effective for prevention when using FGAs D and temporary use for up to several weeks after starting treatment is desirable 2D.
Avoid high‐titer/high‐dose FGAs and select SGAs 1C. Alternatively, it is desirable to select medium‐titer or low‐titer FGAs when SGAs are not possible to use 2D. No recommendation is made for a specific SGA.
Selecting SGAs is recommended over FGAs 1D.
Prevention of tardive dystonia
There is almost no evidence at this stage on drugs that are effective for preventing tardive dystonia, so no recommendation is made.

Recommendation

It is recommended to suspend antipsychotics and conduct physical treatment such as systemic monitoring and infusion 1D.
Dantrolene use is recommended since it reduces the mortality rate when compared to patients who do not receive specific treatment 1D. However, caution is required as it may occasionally cause serious liver damage D.
Bromocriptine use may worsen psychiatric symptoms, D but its use is recommended since it significantly reduces the mortality rate when compared to patients who do not receive specific treatment 1D.
ECT does not result in any significant differences when compared to patienys who do not receive specific treatment but tends to reduce the mortality rate D. Its effects are expected to improve psychiatric symptoms D, so it is desirable to administer ECT 2D.
Switching from olanzapine to risperidone, perphenazine, or aripiprazole suppresses weight gain C. However, it is desirable to consider the benefits and harm, as well as the course of treatment to date and antipsychotic drug use history when olanzapine is effective against psychiatric symptoms. Before switching the drug, it is also recommended to discuss with the patient the possibility of recurrence and relapse 2C.
Switching from olanzapine to quetiapine does not have weight reduction effects while it worsens treatment continuation rate C. Therefore, it is not desirable to switch to quetiapine 2C.
Reducing the dose of olanzapine is unlikely to prevent weight gain D. For this reason, reducing the dose is not desirable 2D.
Metformin has been shown to have a weight reduction effect D. However, its indications on the package insert are limited. No recommendation is made (no recommendation, D).
Nizatidine D, amantadine D, and atomoxetine D have not been shown to affect weight reduction. Their use is not desirable 2D.
Topiramate has a weight reduction effect D but it also has the possibility of significant side effects such as psychomotor arrest, hypersalivation, and dysesthesia D. Therefore, its use is not desirable 2D.
Zonisamide has a weight reduction effect D but it may induce serious side effects such as cognitive dysfunction D. Its use is not desirable 2D.

Contents of the original publication

The section headings of the original.

English translation team: (affiliation as of May 2021)
English translation team: (COI as of 2018‐2020)
Before reading this guideline
Introduction
Background of creating the Guideline for Pharmacological Therapy of Schizophrenia
Members of the task force at the time of the initial creation of the Guideline for Pharmacological Therapy of Schizophrenia at 2015
Task force member roles
Conflict‐of‐interest information
Status of Guideline for Pharmacological Therapy of Schizophrenia Task Force meetings
Interim reports and public discussions
Disclaimer
Basic principles of this guideline
Procedure for creating this guideline
Precautions when using this guideline
Regarding diagnosis of schizophrenia
General theory of pharmacological therapy of schizophrenia
The limits of evidence
Use of the latest edition and overall reading
Drug name notation
Explanation of main terms
Revisions
July 31, 2016 Revision
April 18, 2017 Revision
May 23, 2017 Revision
November 22, 2017 Revision
Chapter 1: First‐episode psychosis
Introduction
CQ1‐1 Which antipsychotics are recommended for the treatment of first‐episode psychosis?
CQ1‐2 What is the optimal dose of antipsychotics for first‐episode psychosis?
CQ1‐3 What is the optimal period for determining the therapeutic response of antipsychotics in first‐episode psychosis?
CQ1‐4 What is the optimal treatment duration for antipsychotics for preventing the recurrence of first‐episode psychosis?
Chapter 2: Recurrence and relapse
Introduction
CQ2‐1 Which is more appropriate, increasing the dose of the current antipsychotic or switching to another one?
CQ2‐2 Which antipsychotics have evidence of usefulness and recommended dose at the time of recurrence/relapse of schizophrenia?
CQ2‐3 Is Antipsychotic combination therapy more useful than monotherapy at the time of recurrence/relapse?
CQ2‐4 Which is more appropriate, monotherapy of antipsychotics, or concomitant therapy of psychotropics other than antipsychotics in terms of efficacy and side effects at the time of recurrence/relapse of schizophrenia?
Chapter 3: Maintenance treatment Introduction
CQ3‐1 Should antipsychotic medication be discontinued or continued in the maintenance phase?
CQ3‐2 Which antipsychotics are favorable for reducing the relapse rate or for continuing treatment in the maintenance phase?
CQ3‐3 Are long‐acting injections of antipsychotics more useful than oral drugs? What kind of patients should LAI be used?
CQ3‐4 Is reducing the dose of antipsychotics useful in the maintenance phase?
CQ3‐5 What is the appropriate dosing interval for oral antipsychotic drug treatment for stable patients in the maintenance phase ?
Chapter 4: Treatment resistance Introduction
CQ4‐1 Is clozapine treatment useful for patients with treatment‐resistant schizophrenia?
CQ4‐2 What is the recommended course of action when one or more side effects occur in patients in whom clozapine treatment is effective?
CQ4‐3 Which concomitant therapy should be selected when the effects of clozapine are insufficient?
CQ4‐4 Is modified electroconvulsive therapy (m‐ECT) useful for treatment‐resistant schizophrenia when clozapine is not used?
CQ4‐5 What are effective treatments other than those with clozapine or electroconvulsive therapy for treatment‐resistant schizophrenia?
Chapter 5: Other clinical problems Introduction
CQ5‐1 What pharmacological therapies are recommended for psychomotor agitation?
CQ5‐2 What treatment methods are recommended for catatonia in schizophrenia?
CQ5‐3 What kinds of pharmacological therapies are effective against depressive symptoms of schizophrenia?
CQ5‐4 Is there a recommended pharmacotherapy for cognitive impairment in schizophrenia?
CQ5‐5 Is there a recommended pharmacotherapy for psychosis‐related polydipsia and water intoxication?
CQ5‐6 What are the recommended treatment and prevention methods for extrapyramidal symptom (EPS)?
CQ5‐7 Is there a recommended treatment method for neuroleptic malignant syndrome?
CQ5‐8 Is there a recommended treatment method for weight gain due to antipsychotics?

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