PICO Search Assignment #1

Tiffany Liang

PATIENT PROBLEM/SETTING

40 yo female patient presents to the inpatient psychiatric unit for a schizophrenia episode. Patient has an 18 year history of schizophrenia and currently takes Risperidone 1mg 2x PO q daily.

SEARCH QUESTION: Does the use of dual 2nd generation anti-psychotics reduce the risk of hospital readmissions in schizophrenic patients compared to use of monotherapy 2nd generation anti-psychotics?

QUESTION TYPE: What kind of question is this? (boxes now checkable in Word)

☐Prevalence ☐Screening ☐Diagnosis

☐Prognosis ☒Treatment ☐Harms

• The first choice of study would be a meta-analysis or systematic review as they are regarded as the highest level of study. Meta-analysis systematically reviews the findings of several independent studies. Systematic review is similar in that it proposes a research question and that collects and summarizes all relevant data with eligible criteria. In conclusion, both types of study gathers a larger pool of data to provide more information and greater overview on the topic discussed.

• If these two studies are not available, a randomized control trial would be the next best choice as there is a control and study. In this situation, the control would be one 2nd generation anti-psychotic and the study would be the use of two 2nd generation anti-psychotics. Randomized control trials offers carefully planned experiments and reduces the risk of bias in order to compare the two groups studied and gauge if the study is effective.

PICO SEARCH TERMS:

P	I	C	O
Schiophrenia	Dual 2nd-generation anti-psychotics	2nd-generation anti-psychotic mono therapy	Hospital Readmission
Schizophrenic Patients	Schizophrenia polypharmacy	One 2nd-generation anti-psychotic	Schizophrenic Episode
Psychotic Patients	Risperidone and Ariprazole	Single 2nd-generation anti-psychotic	Reduction in hallucinations
Hallucinatory Patients	Multiple anti-psychotics	Only Risperidone	Relief of hallucinations
Psychosis	Multiple 2nd-generation anti-psychotics	Only Ariprazole	Schizophrenia Relapse

SEARCH TOOLS & RESULTS

PubMed:

• Schizophrenia Dual Anti-Psychotic (Filters : Meta Analysis, Systemic Review, RCT, 2010-present) – 93

• Schizophrenia anti-psychotic combination (Filters : Meta Analysis, Systemic Review, RCT, 2010-present) – 45
• Dual Antipsychotics (Filers : Meta Analysis, Systemic Review, RCT, 2010-present) – 85

Cochrane :

• Dual Therapy Schizophrenia (Filters: Meta analysis, Systemic Review, RCT, 2010-Present) – 26
• Antipsychotic Polypharmacy (Filters: Meta analysis, Systemic Review, RCT, 2010-Present) – 2

JAMA :

• Dual antipsychotics (Filters : Psychiatry) – 0
• Antipsychotic Polypharmacy (Filters : Psychiatry) – 25

Initially, I limited my search parameters to meta-analyses, systematic reviews, and randomized controlled studies as they are considered the highest level of study. A filter for the past ten years was also applied so that the most relevant data could be gathered. However, many of these studies only followed schizophrenia patients for a short period of time. There was no concrete evidence of whether dual anti-psychotic therapy was beneficial in reducing hospital readmission as the subjects were not studied for long enough. This expanded my search to include other types of studies with no date range to see if a study existed to allow for a longer follow-up period.

ARTICLES

1. Clozapine Combined with Different Anti-Psychotic Drugs for Treatment-Resistant Schizophrenia

Citation: Barber S, Olotu U, Corsi M, Cipriani A. Clozapine combined with different antipsychotic drugs for treatment-resistant schizophrenia. Cochrane Database Syst Rev. 2017 Mar 23;3(3):CD006324. doi: 10.1002/14651858.CD006324.pub3. PMID: 28333365; PMCID: PMC6464566.

Type of article:  Meta-Analysis

Abstract:  Background: Clozapine is reserved for treatment-resistant schizophrenia due to its adverse effect profile. However, 40 – 70% of patients continue to not respond to Clozapine. Combination therapy with another 2nd generation anti-psychotic is a suggested alternative treatment strategy.  Materials and Methods: This study used the Cochrane Schizophrenia Group’s Study-Based Register of Trials and MEDLINE to search for randomized control trails exploring combination anti-psychotic therapy with Clozapine and another anti-psychotic. The trial parameters included both genders, aged 18 years or older, and with treatment-resistant schizophrenia. Results were assessed by observing clinical response in mental state and adverse effects (i.e. weight gain).  Results: 5 studies with 309 participants were reviewed. Studies were conducted by comparing dual therapy with Clozapine and a 1st generation anti-psychotic versus Clozapine and a 2nd-generation anti-psychotic. By combining Clozapine with Aripiprazole vs. Clozapine with Haloperidol, the study found no long-term difference in reducing schizophrenia episodes (95% Cl -8.48 to -1.32). Significant benefit in mental status and reduction in adverse effects was only observed when Clozapine was combined with Quetiapine for a short-term period (95% Cl -1.38 to -0.42). Another study combined Clozapine and Risperidone to show no difference in treatment outcome (95% CL 0.40 – 1.68). Conclusion: In this study, it was determined that there was no significant benefit in using dual 2nd-generation anti-psychotic therapy in treatment-resistant schizophrenia patients due to a limited number of studies and inconsistent participation by patients. As several participants left early, the study ultimately showed low-quality evidence.

Key points: In the included studies, there was no clear benefit in taking two 2nd generation anti-psychotics 1/5 studies showed short term benefit in taking Clozapine and Quetiapine for short-term use only 4/5 studies showed no benefit in terms of mental state and reduction in adverse effects Further trials with better experimental setup must be conducted to establish a clear relationship between the use of two 2nd generation anti-psychotics in treating schizophrenia long-term.

Why I chose it: This article was chosen because it clearly pertained to the use of two second generation anti-psychotics for treatment-resistant schizophrenia patients. This proposed a study that matched the clinical question for this PICO study. Furthermore, this article was a meta-analysis conducted in 2017 that included several studies. This allowed for a greater overview of the subject with richer and relevant sources of data.

2. Combining Anti-Psychotic Medication for the Treatment of Schizophrenia

Citation: Ortiz-Orendain J, Castiello-de Obeso S, Colunga-Lozano L, Hu Y, Maayan N, Adams CE. Antipsychotic combinations for schizophrenia. Cochrane Database of Systematic Reviews 2017, Issue 6. Art. No.: CD009005. DOI: 10.1002/14651858.CD009005.pub2

Type of article:  Meta -Analysis

Abstract:  Objective: This study was performed to see if there was improved patient outcome in using multiple anti-psychotics versus a single anti-psychotic in treating schizophrenia patients.  Materials and Methods: Sixty-Two trails were studied for this review using Randomized Controlled Trials from the Information Specialist of the Cochrane Schizophrenia Group in 2010, 2012, 2016. There was no parameters in terms of age or gender of patient.  Results: The combination of antipsychotics showed some improvement in the treatment of schizophrenia in contrast to taking only one anti-psychotic. The most significant benefit was found using Clozapine and a typical anti-psychotic. However, combination therapy showed no significant benefit in preventing relapse of schizophrenia. Conclusions: This study showed some improvement in the use of combination anti-psychotic therapy for short-term treatment, but not relapse or re-hospitalization. This is likely due to the fact that the study was performed over a short period of time whereas schizophrenia is a long-term disease that requires extensive treatment and observation.

Key points: Combination of Clozapine and typical anti-psychotic showed short-term benefit in treating schizophrenia Combination of two anti-psychotics did not affect relapse and re-hospitalization of schizophrenia patients Study did not provide specific parameters in participants and only looked at short-term outcomes. Conclusion cannot determine the efficacy of using two anti-psychotics in preventing relapses of schizophrenia.

Why I chose it: I chose this article because it specifically looked into the use of two anti-psychotics verse one anti-psychotic and its affects on hospitalization. This specifically looked into the question of whether the use of dual therapy reduced hospital re-admissions instead of only at initial treatment outcomes.

3. Association of Antipsychotic Polypharmacy vs. Monotherapy Psychiatric Rehospitalization Among Adults with Schizophrenia

Citation: Tiihonen J, Taipale H, Mehtälä J, Vattulainen P, Correll CU, Tanskanen A. Association of Antipsychotic Polypharmacy vs Monotherapy With Psychiatric Rehospitalization Among Adults With Schizophrenia. JAMA Psychiatry. 2019;76(5):499–507. doi:10.1001/jamapsychiatry.2018.4320

Type of article:  Cohort Study

Abstract:  Objective: This study was conducted to summarize and compare the efficacy of using a combination pharmacologic approach in contrast to a monotherapy approach to reducing schizophrenia hospital readmissions.  Data Sources: A systemic search of PubMed and PsycInfo was performed leading up to the year of 2014. Methods & Materials : 62, 250 patients were studied. 31,257 were men with a median age of 45.6. They accounted for all persons with schizophrenia treated in an inpatient setting in Finland from 1972-2014. Patients were tracked using the discharge register maintained by the National Institute of Health and Welfare.  Results: The combination of Clozapine and Aripiprazole showed the lowest risk of psychiatric re-hospitalization than just clozapine alone (HR 0.86, 95% Cl 0.75 to 0.89, P < .001) The benefits of dual 2nd generation anti-psychotic therapy was more evident in patients who experienced their first schizophrenic episode (HR 0.78, 95% Cl 0.63 – 0.96). Other drugs combinations studied were clozapine, aripirazole and a partial D2 receptor agonist. This showed an improvement in negative symptoms, reduced weight gian, but presented with increased prolactin level. Another combination studied was of 2 dopamine D2 antagonists. This too, presented with greater prolactin levels but less insomnia.  Conclusions: Combination of Clozapine and Aripiprazole showed the greatest benefit in reducing schizophrenia re-hospitalization. However, this study did not account for additional add-on treatments that may have contributed to the long-term stabilization of the patient.

Key points: All patients with schizophrenia in the country of Finland were followed from 1972 – 2014 Clozapine and Aripiprazole dual therapy showed the greatest efficacy in reducing hospital re-admissions than Clozapine mono therapy (lowered readmission by 14%)

Why I chose it: This article was chosen as it specifically explored antipsychotic polypharmacy vs mono therapy and was able to assess a large group of schizophrenia patients over a long period of time. The combination of Clozapine and Aripiprazole versus Clozapine alone applied directly to the clinical case scenario. However, the main reason this article was valuable was that it was able to follow-up patients through the course of disease. Compared to the previous two articles, this study presented a thorough perspective of whether patients were readmitted during the course of their lifetime for schizophrenia relapse.

What is the clinical “bottom line” derived from these articles in answer to your question?

According to UpToDate, Schizophrenia In Adults : Maintenance Therapy and Side Effect Management, schizophrenia treatment should first be started with the lowest therapeutic dose of a 2nd anti-psychotic medication. 2nd anti-psychotic medications are the first choice as they produce less extrapyramidal symptoms (dystonia, Parkinsonism, akathisia, tardive dyskinesia) due to their lower affinity for dopamine receptors. Risperidone and Aripiprazole are the suggested initial choices of medication as they present with the least adverse effect profile within the class of 2nd generation anti-psychotics. If the trial fails, an alternative anti-psychotic is initiated. Finally, if both trials fail, Clozapine is started. Although Clozapine is highly effective in treating psychotic symptoms, it is reserved for later use due to its severe adverse effect profile such as agranulocytosis and rhabdomyolysis. As schizophrenia is a life-long disease with severely debilitating symptoms, the field of medicine is constantly looking for a better combination of treatment options or new drugs in order to more effectively treat schizophrenia. For this reason, the exploration of using dual 2nd generation anti-psychotic versus a single 2nd generation anti-psychotics is investigated in this PICO study. 

The clinical bottom line of the following studies suggests that there is no concrete correlation in the use of dual 2nd generation anti-psychotics in reducing hospital readmissions for schizophrenia patients. Two of the three articles showed evidence in combining Clozapine and another anti-psychotic in treating schizophrenia patients (Barber 2017; Ortiz-Orendein 2017). However, they both presented with the limiting factor of being conducted over a short period of time. This provides inconclusive evidence as schizophrenia is a long-term disease. The studies weren’t long enough to establish if there was re-hospitalization during a patient’s lifetime. The third article presented with stronger evidence in the benefit of using dual 2nd generation anti-psychotic therapy as it followed patients for the entirety of their life (Tiihonen, 2019). Although there was a correlation between using dual therapy and reduction in hospital readmissions, the sample size was limited to the country of Finland. This is a very small population without a large range of diversity. Therefore, the findings cannot be applied to the general public. In conclusion, these articles suggest that the recommended treatment remains what is advised in UptoDate.  More long-term studies over broader study groups would be needed to provide conclusive evidence that dual 2nd generation anti-psychotic therapy reduces schizophrenia hospital readmissions.