Appendix B. Search Strategies, Study Selection, and Search Results
AHRQ Review
The Agency for Healthcare Research and Quality’s (AHRQ) systematic review Treatments for Schizophrenia in Adults (McDonagh et al. 2017) served as the predominant source of information for this guideline. Databases that were searched are Ovid MEDLINE® (PubMed®), the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and PsycINFO®. Results were limited to English-language, adult (18 and older), and human-only studies. The search varied by key question because high-quality systematic reviews were used as a starting point for the review. For key question 1, search dates for first-generation antipsychotic medications (FGAs) versus second-generation antipsychotic medications (SGAs) began in 2011 and for SGAs versus SGAs began in 2013. Key question 2 did not restrict the start date. All searches were conducted through February 1, 2017. The search strategies used can be found in Appendix A of the AHRQ review (McDonagh et al. 2017).
The AHRQ review (McDonagh et al. 2017) adhered to the procedures outlined in the AHRQ Methods Guide for Effectiveness and Comparative Effectiveness Reviews (Agency for Healthcare Research and Quality 2014). Recent, comprehensive, good- or fair-quality systematic reviews served as a primary source of evidence, supplemented by information from randomized controlled trials (RCTs) published since the systematic reviews or when no systematic reviews were available. For assessment of harms of treatment, systematic reviews of observational trials were also included. Eligibility for inclusion and exclusion of articles adhered to preestablished criteria. Specifically, the AHRQ review included articles that had at least 12 weeks of follow-up and were conducted in outpatient settings in countries that were relevant to the United States’ health care system. Articles that addressed benefits of treatment were included if at least 90% of the sample had a diagnosis of schizophrenia (or schizophreniform disorder), with a schizophrenia spectrum disorder in at least 50% of the sample (minimum sample size > 50) for studies of harms of treatment. For key questions that related to antipsychotic treatment, all of the SGAs were included; for FGAs, studies on fluphenazine, haloperidol, and perphenazine were included. Only head-to-head comparison studies were included. For studies of psychosocial and other nonpharmacological interventions, studies were included if they compared usual care, standard care, treatment as usual, or a waitlist control group to active treatment with assertive community treatment, cognitive adaptive training, cognitive-behavioral therapy, cognitive remediation, early interventions for first-episode psychosis, family interventions, intensive case management, illness self-management training, interventions for co-occurring schizophrenia and substance use, psychoeducation, social skills training, supported employment, or supportive psychotherapy.
Using these criteria, titles and abstracts were reviewed by two individuals (McDonagh et al. 2017). Full-text articles were retrieved if either reviewer felt inclusion was warranted. Full-text articles were also evaluated by two reviewers, and disagreements about inclusion were resolved by consensus. Included studies are listed in Appendix B of the AHRQ review, and excluded studies (with the reason for exclusion) are listed in Appendix C of the AHRQ review (McDonagh et al. 2017). For key question 1 on antipsychotic treatment, 698 citations were identified, 519 of which were excluded on the basis of title and abstract review, yielding 179 full-text articles that were reviewed, of which 38 were included in the final AHRQ review. For key question 2 on psychosocial and other nonpharmacological interventions, 2,766 citations were identified, 1,871 of which were excluded on the basis of title and abstract review, yielding 895 full-text articles that were reviewed, of which 53 were included in the final AHRQ review. Additional summary information about the included studies is shown in Table B-1, and additional details can be found in the AHRQ review (McDonagh et al. 2017).
Systematic reviews | Number of publications | Number of trials in systematic reviews | Number of subjects in systematic reviews | Number of additional trials | Number of publications | Number of subjects in additional trials | Total number of subjects | |
|---|---|---|---|---|---|---|---|---|
| FGA vs. SGA | 1 | 2 | 111 | 118,503 | 5 | 7 | 1,055 | 119,558 |
| SGA vs. SGA | 1 | 1 | 138 | 47,189 | 24 | 28 | 6,672 | 53,861 |
| Assertive community treatment | 1 | 1 | 14 | 2,281 | 1 | 1 | 118 | 2,399 |
| Cognitive adaptive training | 0 | 0 | 0 | 0 | 3 | 4 | 290 | 290 |
| Cognitive-behavioral therapy | 3 | 3 | 89 | 7,154 | 5 | 6 | 823 | 7,977 |
| Cognitive remediation | 2 | 2 | 57 | 2,885 | 4 | 5 | 341 | 3,226 |
| Early intervention for first-episode psychosis | 0 | 0 | 0 | 0 | 4 | 9 | 2,363 | 2,363 |
| Family interventions | 1 | 1 | 27 | 2,297 | 6 | 8 | 562 | 2,859 |
| Intensive case management | 1 | 1 | 10 | 1,652 | 1 | 1 | 77 | 1,729 |
| Interventions for schizophrenia and co-occurring SUD | 1 | 1 | 32 | 3,165 | 0 | 0 | 0 | 3,165 |
| Illness self-management | 1 | 1 | 13 | 1,404 | 1 | 1 | 210 | 1,614 |
| Psychoeducation | 1 | 1 | 10 | 1,125 | 0 | 0 | 0 | 1,125 |
| Social skills training | 0 | 0 | 0 | 0 | 3 | 4 | 433 | 433 |
| Supported employment | 1 | 1 | 14 | 2,265 | 2 | 3 | 1,477 | 3,742 |
| Supportive psychotherapy | 1 | 1 | 5 | 822 | 0 | 0 | 0 | 822 |
| Abbreviations. FGA = first-generation antipsychotic; SGA = second-generation antipsychotic; SUD = substance use disorder. | ||||||||
| Source. Adapted from McDonagh et al. 2017. | ||||||||
Studies used in the Agency for Healthcare Research Quality review
For included studies, abstracted information was verified for accuracy and completeness by a second individual and included citation, year, study design, setting, funding source, country, sample size, eligibility criteria, clinical characteristics, and other characteristics of the study design, population, intervention, and outcomes (McDonagh et al. 2017). In addition, individual controlled trials and systematic reviews were assessed by two team members with predefined criteria for study quality, yielding ratings of “good,” “fair,” or “poor,” with disagreements resolved by consensus (McDonagh et al. 2017). Included systematic reviews were generally of good quality, whereas additional included studies were generally of fair quality.
Treatment of Neurological Side Effects of Antipsychotic Medications
Additional searches were undertaken to supplement the AHRQ review and to identify studies that addressed approaches to treatment of neurological side effects of antipsychotic medications. Search strategies for MEDLINE (PubMed) and Cochrane Library are shown in Tables B–2 and B–3, respectively. For each search, all available citations were identified from the inception of the database to July 29, 2018, the date when the searches were conducted. A search of MEDLINE yielded 2,980 citations, and a search of the Cochrane Library yielded 2,450. After duplicate citations were removed, titles and abstracts for 4,196 articles were screened by one reviewer (L. J. F.) to identify articles in humans, 18 years of age or older, published in English, that investigated the treatment of antipsychotic-associated dystonia, parkinsonism, akathisia, tardive syndromes, or neuroleptic malignant syndrome. Systematic reviews and meta-analyses were used as a primary source of evidence, and if multiple Cochrane reviews on a topic had been done, only the most recent review was included. For topics on which no systematic review was available, RCTs with a sample size of at least 20 subjects and observational studies with a sample of at least 50 individuals were included. Included studies had a follow-up period of at least 1 week for acute dystonia or neuroleptic malignant syndrome and 8 weeks for other side effects.
ID | Search | Hits |
|---|---|---|
| #1 | Search “Akineton”[TIAB] OR “Amantadine”[MH] OR “Amantadine”[TIAB] OR “Artane”[TIAB] OR “Atropine”[MH] OR “Atropine”[TIAB] OR “Benadryl”[TIAB] OR “Benztropine”[MH] OR “Benztropine”[TIAB] OR “Biperiden”[MH] OR “Biperiden”[TIAB] OR “Bromocriptine”[MH] OR “bromocriptine”[TIAB] OR “Cogentin”[TIAB] OR “Cuvposa”[TIAB] OR “Dantrium”[TIAB] OR “Dantrolene”[MH] OR “Dantrolene”[TIAB] OR “Diphenhydramine”[MH] OR “Diphenhydramine”[TIAB] OR “Glycopyrrolate”[MH] OR “Glycopyrrolate”[TIAB] OR “Nitoman”[TIAB] OR “Procyclidine”[MH] OR “Procyclidine”[TIAB] OR “Robinul”[TIAB] OR “Symmetrel”[TIAB] OR “Tetrabenazine”[MH] OR “Tetrabenazine”[TIAB] OR “Trihexyphenidyl”[MH] OR “Trihexyphenidyl”[TIAB] OR “Xenazine”[TIAB] OR “beta blocker”[TIAB] OR “beta blockers”[TIAB] OR “beta adrenergic antagonist”[TIAB] OR “beta adrenergic antagonists”[TIAB] OR “beta adrenergic blocking”[TIAB] OR “beta adrenergic blocking agent”[TIAB] OR “beta adrenergic blocking agents”[TIAB] OR “adrenergic beta antagonists”[TIAB] OR “propranolol”[TIAB] OR “pindolol”[TIAB] OR “atenolol”[TIAB] OR “inderal”[TIAB] OR “muscarinic antagonists”[MeSH Terms] OR “adrenergic beta antagonists”[MeSH Terms] OR “amantadine”[MeSH Terms] OR “benztropine”[MeSH Terms] OR “diphenhydramine”[MeSH Terms] OR “trihexyphenidyl”[MeSH Terms] OR “propranolol”[MeSH Terms] OR “pindolol”[MeSH Terms] OR “atenolol”[MeSH Terms] | 163,354 |
| #2 | Search “9-hydroxy-risperidone”[TIAB] OR “abilify”[TIAB] OR “antipsychotic agents”[MeSH Major Topic] OR “antipsychotic agents”[MeSH Terms] OR “antipsychotic”[TIAB] OR “antipsychotics”[TIAB] OR “aripiprazole”[NM] OR “aripiprazole”[TIAB] OR “Asenapine”[NM] OR “Asenapine”[TIAB] OR “Chlorpromazine”[MH] OR “Chlorpromazine”[NM] OR “Chlorpromazine”[TIAB] OR “Chlorprothixene”[MH] OR “Chlorprothixene”[NM] OR “Chlorprothixene”[TIAB] OR “Clopixol”[TIAB] OR “Clozapine”[MH] OR “clozapine”[NM] OR “clozapine”[TIAB] OR “clozaril”[TIAB] OR “Consta”[TIAB] OR “Droperidol”[MH] OR “droperidol”[NM] OR “droperidol”[TIAB] OR “Fanapt”[TIAB] OR “Fazaclo”[TIAB] OR “Fluanxol”[TIAB] OR “flupenthixol”[NM] OR “flupenthixol”[TIAB] OR “flupenthixol”[TIAB] OR “fluphenazine depot”[NM] OR “fluphenazine depot”[TIAB] OR “fluphenazine enanthate”[NM] OR “fluphenazine enanthate”[TIAB] OR “Fluphenazine”[MH] OR “Fluphenazine”[TIAB] OR “Geodon”[TIAB] OR “Haldol”[TIAB] OR “haloperidol decanoate”[NM] OR “haloperidol decanoate”[TIAB] OR “Haloperidol”[MH] OR “haloperidol”[NM] OR “haloperidol”[TIAB] OR “Iloperidone”[TIAB] OR “Inapsine”[TIAB] OR “Invega”[TIAB] OR “Largactil”[TIAB] OR “Loxapac”[TIAB] OR “Loxapine”[MH] OR “Loxapine”[NM] OR “Loxapine”[TIAB] OR “Loxitane”[TIAB] OR “Lurasidone”[TIAB] OR “Mellaril”[TIAB] OR “Mesoridazine”[MH] OR “Mesoridazine”[NM] OR “Mesoridazine”[TIAB] OR “Moban”[TIAB] OR “Modecate”[TIAB] OR “Molindone”[MH] OR “Molindone”[NM] OR “Molindone”[TIAB] OR “Navane”[TIAB] OR “olanzapine”[NM] OR “olanzapine”[TIAB] OR “Orap”[TIAB] OR “paliperidone palmitate”[NM] OR “Perphenazine”[MH] OR “Paliperidone”[TIAB] OR “Perphenazine”[NM] OR “Perphenazine”[TIAB] OR “Pimozide”[MH] OR “Pimozide”[NM] OR “Pimozide”[TIAB] OR “Prolixin”[TIAB] OR “quetiapine”[TIAB] OR “Relprevv”[TIAB] OR “Risperdal”[TIAB] OR “Risperidone”[MH] OR “Risperidone”[NM] OR “Risperidone”[TIAB] OR “Saphris”[TIAB] OR “Serentil”[TIAB] OR “Seroquel”[TIAB] OR “Stelazine”[TIAB] OR “Sustenna”[TIAB] OR “Symbyax”[TIAB] OR “Taractan”[TIAB] OR “Thioridazine”[MH] OR “Thioridazine”[NM] OR “Thioridazine”[TIAB] OR “Thiothixene”[MH] OR “Thiothixene”[NM] OR “Thiothixene”[TIAB] OR “Thorazine”[TIAB] OR “Trifluoperazine”[MH] OR “Trifluoperazine”[NM] OR “Trifluoperazine”[TIAB] OR “Trilafon”[TIAB] OR “Zeldox”[TIAB] OR “ziprasidone”[NM] OR “ziprasidone”[TIAB] OR “zuclopenthixol”[TIAB] OR “Zydis”[TIAB] OR “Zyprexa”[TIAB] | 113,808 |
| #3 | Search “akathisia”[TIAB] OR “Akathisia, Drug-Induced”[MH] OR “drug induced parkinsonism”[TIAB] OR “Dyskinesia, Drug-Induced”[MH] OR “dystonic reaction”[TIAB] OR “dystonic reactions”[TIAB] OR “extrapyramidal reactions”[TIAB] OR “extrapyramidal side effect”[TIAB] OR “extrapyramidal side effects”[TIAB] OR “extrapyramidal signs”[TIAB] OR “extrapyramidal syndrome”[TIAB] OR “extrapyramidal syndromes”[TIAB] OR “Neuroleptic Malignant Syndrome”[MH] OR “neuroleptic malignant”[TIAB] OR “tardive dyskinesia”[TIAB] OR “tardive dystonia”[TIAB] OR “neuroleptic induced parkinsonism”[TIAB] OR “medication induced parkinsonism”[TIAB] OR “tardive akathisia”[TIAB] | 16,341 |
| #4 | Search ((“animals”[MeSH Major Topic] OR “animals”[MeSH Terms] OR “animal”[TIAB] OR “animals”[TIAB] OR “rat”[TIAB] OR “mouse”[TIAB] OR “mice”[TIAB] OR “rodent”[TIAB] OR “rodents”[TIAB] OR “rats”[TIAB]) NOT (“humans”[MAJR] OR “humans”[MH] OR “human”[TIAB] OR “humans”[TIAB])) | 4,437,558 |
| #5 | Search “meta analysis”[TIAB] OR “meta analyses”[TIAB] OR “meta analytic”[TIAB] OR “metaanalysis”[TIAB] OR “metaanalysis”[TIAB] OR “systematic review”[TIAB] OR “systematic reviews”[TIAB] OR “meta analysis”[Publication Type] OR “randomized controlled trial”[PT] OR “randomised”[TIAB] OR “randomized”[TIAB] OR “randomisation”[TIAB] OR “randomization”[TIAB] OR “randomly”[TIAB] OR “placebo”[TIAB] OR “sham”[TIAB] OR “trial”[TIAB] OR “groups”[TIAB] | 2,841,422 |
| #6 | Search “controlled clinical trial”[PT] OR “blinded”[TIAB] OR “case control”[TIAB] OR “clinical trial”[TIAB] OR “clinical trials”[TIAB] OR “Cohort Analysis”[TIAB] OR “cohort research”[TIAB] OR “cohort study”[TIAB] OR “cohort trial”[TIAB] OR “comparator group”[TIAB] OR “controlled studies”[TIAB] OR “controlled study”[TIAB] OR “controlled trial”[TIAB] OR “controlled trials”[TIAB] OR “double blind”[TIAB] OR “followup study”[TIAB] OR “longitudinal research”[TIAB] OR “longitudinal study”[TIAB] OR “longitudinal trial”[TIAB] OR “multicenter trial”[TIAB] OR “multicenter trials”[TIAB] OR “naturalistic research”[TIAB] OR “naturalistic study”[TIAB] OR “naturalistic trial”[TIAB] OR “prospective cohort”[TIAB] OR “prospective research”[TIAB] OR “prospective study”[TIAB] OR “prospective trial”[TIAB] OR “retrospective cohort”[TIAB] OR “retrospective research”[TIAB] OR “retrospective study”[TIAB] OR “retrospective trial”[TIAB] OR “single blind”[TIAB] | 1,513,299 |
| #7 | Search (#1 AND #2) OR (#1 AND #3) OR (#2 AND #3) | 15,146 |
| #8 | Search #7 NOT #4 | 11,508 |
| #9 | Search #8 AND (#5 OR #6) | 3,156 |
| #10 | Search “english”[Language] AND #9 | 2,980 |
Strategy for MEDLINE (PubMed) search on treatments for neurological side effects of antipsychotic medications
ID | Search | Hits |
| #1 | “Akineton” OR “Amantadine” OR “Artane” OR “Atropine” OR “Benadryl” OR “Benztropine” OR “Biperiden” OR “bromocriptine” OR “Cogentin” OR “Dantrium” OR “Dantrolene” OR “Diphenhydramine” OR “Glycopyrrolate” OR “Procyclidine” OR “Robinul” OR “Symmetrel” OR “Tetrabenazine” OR “Trihexyphenidyl” OR “Xenazine” OR “beta blocker” OR “beta blockers” OR “beta adrenergic antagonist” OR “beta adrenergic antagonists” OR “beta adrenergic blocking” OR “beta adrenergic blocking agent” OR “beta adrenergic blocking agents” OR “adrenergic beta antagonists” OR “propranolol” OR “pindolol” OR “atenolol” OR “inderal":ti,ab,kw (Word variations have been searched) | 21,056 |
| #2 | “9-hydroxy-risperidone” OR “abilify” OR “antipsychotic” OR “antipsychotics” OR “aripiprazole” OR “Asenapine” OR “Chlorpromazine” OR “Chlorprothixene” OR “Clopixol” OR “clozapine” OR “clozaril” OR “Consta” OR “droperidol” OR “Fanapt” OR “Fazaclo” OR “Fluanxol” OR “flupenthixol” OR “flupenthixol” OR “fluphenazine depot” OR “fluphenazine enanthate” OR “Fluphenazine” OR “Geodon” OR “Haldol” OR “haloperidol decanoate” OR “haloperidol” OR “Iloperidone” OR “Inapsine” OR “Invega” OR “Largactil” OR “Loxapac” OR “Loxapine” OR “Loxitane” OR “Lurasidone” OR “Mellaril” OR “Mesoridazine” OR “Moban” OR “Modecate” OR “Molindone” OR “Navane” OR “olanzapine” OR “Orap” OR “Paliperidone” OR “Perphenazine” OR “Pimozide” OR “Prolixin” OR “quetiapine” OR “Relprevv” OR “Risperdal” OR “Risperidone” OR “Saphris” OR “Serentil” OR “Seroquel” OR “Stelazine” OR “Sustenna” OR “Symbyax” OR “Taractan” OR “Thioridazine” OR “Thiothixene” OR “Thorazine” OR “Trifluoperazine” OR “Trilafon” OR “Zeldox” OR “ziprasidone” OR “zuclopenthixol” OR “Zydis” OR “Zyprexa” | 16,885 |
| #3 | “akathisia” OR “drug induced parkinsonism” OR “dystonic reaction” OR “dystonic reactions” OR “extrapyramidal reactions” OR “extrapyramidal side effect” OR “extrapyramidal side effects” OR “extrapyramidal signs” OR “extrapyramidal syndrome” OR “extrapyramidal syndromes” OR “neuroleptic malignant” OR “tardive dyskinesia” OR “tardive dystonia” OR “neuroleptic induced parkinsonism” OR “medication induced parkinsonism” OR “tardive akathisia” | 2,505 |
| #4 | (#1 and #2) OR (#1 and #3) OR (#2 and #3) | 2,473 |
| Limited to Cochrane Reviews, Other Reviews and Trials | 2,450 |
Strategy for Cochrane Library search on treatments for neurological side effects of antipsychotic medications
Full-text documents were then reviewed by one individual (L. J. F.) to determine whether they met eligibility criteria. For tardive dyskinesia, 12 systematic reviews were available, with 2 reviews of multiple treatment approaches and 1 review each related to anticholinergic medication, cholinergic medication, benzodiazepines, vitamin B6, vitamin E, calcium channel blockers, γ-aminobutyric acid agonists, non-antipsychotic catecholaminergic drugs, miscellaneous treatments, and antipsychotic reduction or cessation. For akathisia, 3 recent systematic reviews were available, with 1 review each related to β-adrenergic blocking agents, anticholinergic agents, and mirtazapine. No additional RCTs or observational studies met inclusion criteria for other treatments of akathisia (e.g., benzodiazepines). For medication-induced parkinsonism, 1 systematic review was available, but evidence was insufficient to draw any definitive conclusions. For acute dystonia, 1 systematic review, 1 RCT, and 1 nonrandomized prospective study examined effects of anticholinergic medications in reducing the likelihood of acute dystonia; however, no studies meeting inclusion criteria examined use of anticholinergic agents as a treatment of acute dystonia. In addition, no studies meeting inclusion criteria were found that addressed treatment of neuroleptic malignant syndrome.
