Schizophrenia is a severe long-term mental health condition that arises due to environmental and genetic factors. Typical symptoms of schizophrenic patients include hallucinations, muddled thoughts and changes in behaviour. Additionally, Schizophrenia is thought to cause discomfort and shortens lifespan by 20 years on average (1).
Diagnosis involves ruling out other psychological disorders and determining that symptoms are not due to drug abuse, medication or another medical condition. Determining a diagnosis may include physical examination, screening and psychiatric evaluation.
Schizophrenia requires a lifelong treatment, even when symptoms have subsided to avoid relapsing, and in most cases is treated by a plethora of antipsychotic medicines with the lowest possible dose in order to manage signs and symptoms safely and with minimal number of serious side effects. In some events, Clozapine is prescribed to multi-drug resistant patients who do not respond to an adequate trial of at least two antipsychotics, at least one of which must be a second generation antipsychotic (SGA). Clozapine is more expensive but is more effective and pose a lower risk of severe negative impacts such as significant neurological problems including movement disorders on patients (2).
However, papers found show that around 50% of the patients who are treated with Clozapine as a mono-therapy do not respond to the treatment. Consequently, co-administration of adjunctive drugs become inevitable to tackle such symptoms that also possess a detrimental effect on the psychosocial aspects of patients. The commonest augmentation agents used in treatment-resistant schizophrenia are Haloperidol, Aripiprazole, Amisulpride, Sulpiride, Risperidone and Lamotrigine.
The aim of this scientific report is to carry out a systematic review of global literature to find citations that compare the effectiveness of each of these agents when administered simultaneously with Clozapine and finding whether if any has a superiority over the other when improving patient’s quality of life. Effectiveness was measured broadly in terms of clinical efficacy and the number of patients who expressed a reduction in symptom severity under the effect of these medications (reduction in (PANSS, SANS, SAPS and BPRS) * scales found in the different papers referenced below and are used for measuring the side effects on patients with schizophrenia). This was very important to look up since it would increase the awareness towards patients who are suffering from schizophrenia, ultimately allowing for better treatment plans to alleviate people’s pain whilst improving their well-being.
*PANSS- positive and negative syndrome rating scale.
BPRS- the brief psychiatric rating scale.
SANS- the scale to measure negative symptoms.
SAPS- the scale to measure positive symptoms.
The topic question was split into concepts as shown in table 1 that resembled specific conditions to be included. Final results generated were further refined by limiting them to several definite criteria. This focuses the citations found resulting in a more manageable number of applicable articles and journals. Inclusion and exclusion criteria listed below were used to constrict the search as shown in table 2.
Table 1: Topic question concepts inputted into search engines.
“Pharmacological augmentation of Clozapine in treatment resistant schizophrenia – is any one augmentation agent better than the others?”
Concept 1 and
Concept 2 and
Concept 3 and
Concept 4
Schizophrenia or psychosis or psychotic disorders.
Clozapine- resistance
augmentation OR addition OR combination
haloperidol AND aripiprazole AND
amisulpride AND
sulpiride AND risperidone AND lamotrigine
Table 2: Inclusion & Exclusion criteria.
Inclusion
Exclusion
Language
Any language other than “English”
Date published
Published prior to 2009
Open to access
Not free to access
Scientific papers found that compares all six augmented drugs with clozapine to clozapine as a monotherapy
Paper focuses specifically on a comparison between Clozapine as monotherapy vs Clozapine + adjunctive agent
Papers that includes head to head trials comparing the six adjunctive agents
Papers that mainly compared electroconvulsive therapy to clozapine resistant patients
A comprehensive research was conducted on the online databases “Scopus”, “PubMed” and “Web of Science” for topic-relevant papers published in the last 10 years. This was done due to the fact that more recent investigations comprise a higher element of accuracy and are more likely to have used updated and validated techniques. Firstly, inputting the keyword “Schizophrenia” which was the base of our review in Scopus, an enormous number of papers were generated. In addition, applying synonymous terms such as “Psychosis” and “Psychotic disorders” has broadened the quest and provided more robust searches to be displayed by making sure that at least one of the terms must be present. This ensured that fewer citations were missed out and therefore enabled the look up to be more credible.
The topic tackled is whether any of the five second-generation antipsychotics and Lamotrigine which is a mood stabilizer are superior to the other when administered simultaneously with clozapine to treatment-resistant patients. Accordingly, using the words “augmentation” which predominantly means the concurrent application of different agents (e.g. mood stabilizers or anticonvulsants) to increase the effectiveness of the primary drug used. Keywords such as “addition” and “combination” which refer to the synchronised use of two or more substances of the same class were also used. This was vital as many citations relevant to the topic does not use the specific term augmentation. Moreover, they both have completely different meanings clinically and might, therefore, narrow the results if only one of them was used (6).
Including all drugs used synergistically in the search engine provided scientific papers that compared between the effectiveness of the six co-stimulatory agents but might also have included other boosting medications. Apparently, electroconvulsive therapy (ECT) is a common secondary remedy in treatment-resistant schizophrenia, and it is completely irrelevant to the investigation question. Consequently, all records that focus on the analysis this remedial treatment were eliminated by “AND NOT” function. However, a massive drop to the number of papers found was noticed which was not ideal as the results displayed an inadequate number of citations to reach a conclusion.
Moreover, it excluded important papers that also included all other six augmentation drugs under investigation with clozapine. Hence, it was decided not to carry over this step and manually read the abstract and methods of each paper to eliminate the papers that solely focused on ECT making the search more trustworthy. Final results yielded were shown below in tables 3 and 4.
Table 3: Table of methods.
Keywords
SCOPUS
PUBMED
WEB OF SCIENCE
( schizophrenia )
184,562
134,599
167,262
( schizophrenia ) OR
( psychosis ) OR ( psychotic AND disorders ) )
312,476
185,303
204,875
( schizophrenia ) OR
( psychosis ) OR
( psychotic AND
disorders ) ) ) AND
( clozapine AND
resistance )
4,093
584
454
( schizophrenia ) OR
( psychosis ) OR
( psychotic AND
disorders ) ) ) AND
( ( clozapine AND
resistance ) ) AND
( augmentation OR
addition OR
combination)
1,794
174
114
( schizophrenia ) OR
( psychosis ) OR (psychotic AND
disorders ) ) ) AND
( ( ( clozapine AND
resistance ) ) AND
( augmentation OR
addition OR
combination) ) AND
( haloperidol AND
aripiprazole AND
amisulpride AND
sulpiride AND
risperidone AND
lamotrigine )
38
1
1
( schizophrenia ) OR ( psychosis ) OR ( psychotic AND
disorders ) ) ) AND
( ( ( clozapine AND
resistance ) ) AND
( augmentation OR
addition OR
combination) ) AND
( haloperidol AND
aripiprazole AND
amisulpride AND
sulpiride AND
risperidone AND
lamotrigine ) ) AND NOT ( electroconvulsive AND therapy )
14
38
1
1
Table 4: Refining results.
Keywords
SCOPUS
PUBMED
WEB OF SCIENCE
AND ( LIMIT-TO 2014, 2013, 2012, 2010 )
27
1
1
AND ( LIMIT-TO ( LANGUAGE,”English” ) )
25
1
1
The title, abstract and methodology of each paper were then read to get rid of irrelevant citations as well as papers that could not be viewed in full text. Out of the 25 papers found on Scopus, only nine papers (3-11) were found relevant because the majority of articles focused on the guidelines of administration, neuropsychopharmacology and the effect on the neurotransmitter systems rather than their effectiveness comparison. In addition, some papers were only discussed one SGA.
Repeating the exact same procedure on the other databases yielded the same one paper that was also found on Scopus (4).
Results and discussion
Overall, all papers listed in table 5 agree that clozapine remains the most important and effective drug for schizophrenia. The majority mentioned that SGAs might help reduce the negative symptoms of schizophrenia but further head to head trials are required to find which one is surpassing . Some papers came up with a verdict. For instance, paper 1 found that aripiprazole would be the most effective when reducing the negative symptoms of schizophrenia. Paper 2 deducted that there are no significant differences between these drugs. Paper 5 has shown that amisulpride was noticeably more curing. It also shows that aripiprazole and lamotrigine show improvements in the symptoms displayed by schizophrenic patients. Paper 6 does not give a definite agreement on the efficiency of clozapine adjuncts, but it disagrees with the use of risperidone and lamotrigine unlike paper 5. Conversely, paper 9 supports the use of risperidone. To conclude, results show no clear consensus on the most optimal SGA. The answer to this question is still under investigation and progress is being made as we can visualise a trend of more recent papers are the ones that started coming up with proposals. It was difficult to undertake a formal meta-analysis and derive a conclusion due to contradictions and inconsistency of the scales used in different resources making it difficult to combine them.
Table 5: Research Paper Details & Results.
Title of the paper
Author(s)
Date of publishing
Aims of the research
Methodology
Conclusion
Paper 1: Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis (3)
Dan J Siskind
Michael Lee
Arul Ravindran
Qichen Zhang
Evelyn Ma
Balaji Motamarri
Steve Kisely
2018
To conduct a literature search to find the effectiveness of different augmentation agents administered simultaneously with clozapine to patients with clozapine monotherapy resistance.
Online databases such as PubMed, Psyc Info, Embase, Cochrane Database, Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database were used to look for RCTs with different combination approaches administered to patients not responding adequately to clozapine solely. Pairwise meta-analyses of within-class interventions and frequentist mixed treatment comparisons to differentiate treatment effectiveness. 46 studies of 25 interventions were found.
Results have shown that aripiprazole is the most effective augmentation agent for psychosis symptoms (standardised mean difference: 0.48; 95% confidence interval: −0.89 to −0.07) fluoxetine (standardised mean difference: 0.73; 95% confidence interval: −0.97 to −0.50) and, sodium valproate (standardised mean difference: 2.36 95% confidence interval: −3.96 to −0.75).
Paper 2: Clozapine combined with different antipsychotic drugs for treatment-resistant schizophrenia (4)
Barber S
Olotu U
Corsi M
Cipriani A
2017
To test various combinations of clozapine with various second generation antipsychotics and enhancers, investigating their clinical effectiveness and safety on treatment-resistant schizophrenia patients.
The Cochrane Schizophrenia Group Trials Register in August 2015 and January 2016 was investigated and 5 clinical studies involving 309 adults were found. They were diagnosed either with schizophrenia and resistant to clozapine. The investigations compared clozapine combined with the adjunctive antipsychotic drugs such as haloperidol, aripiprazole, amisulpride, lamotrigine, sulpiride, ziprasidone and risperidone.
This paper has shown no significant differences between augmentation drugs for clinically significant responses in mental state. Additionally, the quality of evidence was low and results were therefore less reliable. Furthermore, due to the narrow availability of studies, we were unable to undertake a formal meta‐analyses.
Paper 3: New therapeutic approaches for treatment-resistant schizophrenia (5)
Seiya Miyamoto
L. Fredrik Jarskog
W. Wolfgang Fleischhacker
2014
This study presents review of different pharmacological strategies for treatment-resistant patients.
Augmentation of clozapine with a second generation antipsychotics and other enhancers while examining their effect on (n) number of patients which is different in each experiment. For example, n=734. Negative symptoms in schizophrenic subjects were assessed to measure the effectiveness of the enhancing drugs.
Clozapine remains the most important and effective drug. Augmentation strategies to clozapine for treatment-resistant patients have yet to be supported by further experimented evidence.
Paper 4: Augmentation strategies in partial responder and/or treatment-resistant schizophrenia patients treated with clozapine (6)
Muscatello MR
Bruno A
De Fazio P
Segura-Garcia C
Pandolfo G
Zoccali R.
2014
This research combines the results of a review investigating different augmentation strategies for treatment-resistant schizophrenic patients with a focus on studies conducted over 24 years, between 1990 and 2014.
PubMed, CINAHL, EMBASE Psych INFO, AgeLine and Cochrane Database of Systematic Reviews were searched for question-related studies. Search terms included ‘clozapine augmentation’, ‘clozapine and add-on’ and ‘treatment-resistant schizophrenia’. Evidence on CLZ augmentation with antipsychotics, antidepressants, mood stabilizers and other agents were investigated and reviewed .
Although clozapine is considered the drug of choice for treatment-resistant schizophrenic patients, a large number of patients show a partial or no response to it, resulting in increased healthcare cost and poor quality of life for affected individuals. A plethora of drugs were classified as clozapine adjunctive agents without demonstrating a compelling efficacy in treating refractory schizophrenia symptoms. More research is critical to assess the effectiveness and safety of these augmentation strategies in eliminating these symptoms.
Paper 5: Clozapine combinations in treatment-resistant schizophrenia patients (7)
Vladimir Lerner
Chanoch Miodownik
2012
To provide an overview of the literature concerning the combination of clozapine with different psychotropic medications or procedure in management of resistant schizophrenia and schizoaffective patients who do not or partially respond to clozapine.
For this aim, we performed a systematic literature search in the MEDLINE database for the years ranging from 1970 to March 2012 to identify all publications dealing with assessment of efficacy and safety of adjunctive agents in clozapine-resistant schizophrenic or schizoaffective patients.
Some strategies of augmentation or combination used for clozapine treatment-resistant chronic schizophrenia patients may be useful and relatively safe. Among antipsychotics, clozapine-amisulpride combination showed strong evidence-based support for these patients. Clozapine-aripiprazole maybe promising co-treatment. Augmentation of clozapine with lamotrigine among mood stabilizers among other strategies also seem to be promising attitude. However, further studies are needed to confirm the effectiveness and safety. These data suggest that, at least, under certain circumstances, clozapine combinations may be superior to antipsychotic monotherapy regarding all- causes for discontinuation and general measures of efficacy.
Paper 6: Clozapine resistance: Augmentation strategies (8)
Porcelli S
Balzarro B
Serretti A
2012
In the present paper we critically reviewed literature data regarding the efficacy and safety of adjunctive agents in CLZ-resistant schizophrenics. The following classes of agents were considered: 1) antipsychotics, 2) antidepressants, 3) mood stabilizers, 4) other agents (e.g. fatty acid supplement and glutamatergic agents), 5) electroconvulsive therapy (ECT). For lamotrigine and risperidone sufficient data were available to perform a meta-analysis.
A Medline literature search covering a 20-year period was performed. For the meta-analysis, data were entered and analyzed with the Cochrane Collaboration Review Manager Software (RevMan version 5).
62 pertinent studies were identified, including 1556 schizophrenic or schizoaffective patients. Among treatments investigated, there is evidence for CLZ augmentation with 1) amisulpride and aripiprazole, 2) mirtazapine and 3) ethyl eicosapentaenoic acid (E-EPA). Although promising, ECT augmentation needs further validation. The meta-analyses did not support either the use of risperidone or lamotrigine as CLZ adjunct.
The meta-analyses did not support either the use of risperidone or lamotrigine as CLZ adjunct. Conclusion: Overall, there is scarce evidence of efficacy and safety as regards adjunctive strategies for CLZ-resistant patients. However, several limitations do not allow to draw any definitive conclusion; among these we underline the small sample size of clinical
trials, the variable definitions of CLZ resistance, the heterogeneity of outcome measures and methodological designs.
Paper 7: Treatment-resistant schizophrenia: Evidence-based strategies (9)
Susanne Englisch
Mathias Zink
2012
To investigate the effect of combining clozapine with second-generation antipsychotic agents, antidepressants and mood stabilisers to assess their effectiveness on reducing the negative symptoms of schizophrenic symptoms.
We conducted a comprehensive search of the online databases “Medline OVID”, “The Cochrane Library”, “PubMed” and “scholar.google.com” for topic-related articles published by November 2011. The terms (schizophrenia OR psychotic disorders OR psychosis) were linked with (combination OR augmentation OR add-on OR addition) as well as (antipsychotic agents OR anti-depressive agents OR lithium OR anticonvulsants). In addition, we evaluated currently ongoing subject-related studies on the online database www.clinicaltrials.gov.
In cases of partial response, the combination with second generation agents such as sulpiride, amisulpride,
aripiprazole, ziprasidone and risperidone are justified in order to supplement its
antidopaminergic properties. Clear differential indications should be elaborated by future head-to-head-trials.
Paper 8: Polypharmacy in schizophrenia (10)
Mathias Zink
Susanne Englisch
Andreas Meyer-Lindenberg
2010
This review summarizes the evidence of combined antipsychotic treatment strategies and the augmentation of antipsychotics with mood stabilizers, antidepressants and experimental substances and assessing the negative symptoms and comorbid major depressive episodes.
Publications accessible in public databases (Medline/Ovid, Google, http://www.clinicaltrials.gov) up to October 2009 were assessed.
In general, rigorous data on combination therapy in schizophrenia are rare and further randomized controlled trials, naturalistic trials and head-to-head-trials are necessary. Some evidence supports a combination of antipsychotics and antidepressants for negative symptoms
and comorbid major depressive episodes. The add-on of lithium and mood stabilizers lacks compelling evidence but might be beneficial for specific subgroups. For treatment-resistant cognitive symptoms, antipsychotic medication should be combined with cognitive remediation, as no pharmacological add-on strategy has gained convincing evidence so far. Treatment-emergent positive and/or negative symptoms under clozapine monotherapy might benefit from adding a second atypical substance.
Paper 9: Current perspectives in the treatment of resistant schizophrenia (11)
R. K. Solanki
Paramjeet Singh
Deepti Munshi
2009
This article summarizes the current knowledge base on the diagnosis and management of treatment resistant schizophrenia. This article first looks into the various diagnostic criteria of treatment resistant schizophrenia. Then the literature is reviewed about the pharmacotherapeutics of its management.
Various antipsychotic agents have been used, supposedly to augment the antipsychotic properties of clozapine: amisulpride,aripiprazole, haloperidol, loxapine, olanzapine, pimozide and ziprasidone. The benefit of these augmentation strategies remains inconclusive because they were tested in case series or case reports, which have a low strength of evidence as compared with controlled trials. More robust evidence is derived from four placebo-controlled trials, one with sulpiride and three with risperidone. The study by Shiloh and colleagues showed a significant improvement in positive and negative symptoms in the group that received clozapine plus sulpiride when compared with placebo group.
Clozapine emerges to be the gold standard. In addition, risperidone and high dose olanzapine also emerges as clinically useful options. Other emerging adjunctive treatment options are equally addressed.
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