Klozapin u kombinaciji s različitim antipsihoticima u liječenju shizofrenije otporne na postojeću terapiju
Abstract
Background
Between 40% and 70% of people with treatment‐resistant schizophrenia do not respond to clozapine, despite adequate blood levels. For these people, a number of treatment strategies have emerged, including the prescription of a second anti‐psychotic drug in combination with clozapine.
Objectives
To determine the clinical effects of various clozapine combination strategies with antipsychotic drugs in people with treatment‐resistant schizophrenia both in terms of efficacy and tolerability.
Search methods
We searched the Cochrane Schizophrenia Group's Study‐Based Register of Trials (to 28 August 2015) and MEDLINE (November 2008). We checked the reference lists of all identified randomised controlled trials (RCT). For the first version of the review, we also contacted pharmaceutical companies to identify further trials.
Selection criteria
We included only RCTs recruiting people of both sexes, aged 18 years or more, with a diagnosis of treatment‐resistant schizophrenia (or related disorders) and comparing clozapine plus another antipsychotic drug with clozapine plus a different antipsychotic drug.
Data collection and analysis
We extracted data independently. For dichotomous data, we calculated risk ratios (RRs) and 95% confidence intervals (CI) on an intention‐to‐treat basis using a random‐effects meta‐analysis. For continuous data, we calculated mean differences (MD) and 95% CIs. We used GRADE to create 'Summary of findings' tables and assessed risk of bias for included studies.
Main results
We identified two further studies with 169 participants that met our inclusion criteria. This review now includes five studies with 309 participants. The quality of evidence was low, and, due to the high degree of heterogeneity between studies, we were unable to undertake a formal meta‐analysis to increase the statistical power.
For this update, we specified seven main outcomes of interest: clinical response in mental state (clinically significant response, mean score/change in mental state), clinical response in global state (mean score/change in global state), weight gain, leaving the study early (acceptability of treatment), service utilisation outcomes (hospital days or admissions to hospital) and quality of life.
We found some significant differences between clozapine combination strategies for global and mental state (clinically significant response and change), and there were data for leaving the study early and weight gain. We found no data for service utilisation and quality of life.
Clozapine plus aripiprazole versus clozapine plus haloperidol
There was no long‐term significant difference between aripiprazole and haloperidol combination strategies in change of mental state (1 RCT, n = 105, MD 0.90, 95% CI ‐4.38 to 6.18, low quality evidence). There were no adverse effect data for weight gain but there was a benefit of aripiprazole for adverse effects measured by the LUNSERS at 12 weeks (1 RCT, n = 105, MD ‐4.90, 95% CI ‐8.48 to ‐1.32) and 24 weeks (1 RCT, n = 105, MD ‐4.90, 95% CI ‐8.25 to ‐1.55), but not 52 weeks (1 RCT, n = 105, MD ‐4.80, 95% CI ‐9.79 to 0.19). Similar numbers of participants from each group left the study early (1 RCT, n = 106, RR 1.27, 95% CI 0.72 to 2.22, very low quality evidence).
Clozapine plus amisulpride versus clozapine plus quetiapine
One study showed a significant benefit of amisulpride over quetiapine in the short term, for both change in global state (Clinical Global Impression (CGI): 1 RCT, n = 50, MD ‐0.90, 95% CI ‐1.38 to ‐0.42, very low quality evidence) and mental state (Brief Psychiatric Rating Scale (BPRS): 1 RCT, n = 50, MD ‐4.00, 95% CI ‐5.86 to ‐2.14, low quality evidence). Similar numbers of participants from each group left the study early (1 RCT, n = 56, RR 0.20, 95% CI 0.02 to 1.60, very low quality evidence)
Clozapine plus risperidone versus clozapine plus sulpiride
There was no difference between risperidone and sulpiride for clinically significant response, defined by the study as 20% to 50% reduction in Positive and Negative Syndrome Scale (PANSS) (1 RCT, n = 60, RR 0.82, 95% CI 0.40 to 1.68, very low quality evidence). There were similar equivocal results for weight gain (1 RCT, n = 60, RR 0.40, 95% CI 0.08 to 1.90, very low quality evidence) and mental state (PANSS total: 1 RCT, n = 60, MD ‐2.28, 95% CI ‐7.41 to 2.85, very low quality evidence). No‐one left the study early.
Clozapine plus risperidone versus clozapine plus ziprasidone
There was no difference between risperidone and ziprasidone for clinically significant response (1 RCT, n = 24, RR 0.80, 95% CI 0.28 to 2.27, very low quality evidence), change in global state CGI‐II score (1 RCT, n = 22, MD ‐0.30, 95% CI ‐0.82 to 0.22, very low quality evidence), change in PANSS total score (1 RCT, n = 16, MD 1.00, 95% CI ‐7.91 to 9.91, very low quality evidence) or leaving the study early (1 RCT, n = 24, RR 1.60, 95% CI 0.73 to 3.49, very low quality evidence).
Clozapine plus ziprasidone versus clozapine plus quetiapine
One study found, in the medium term, a superior effect for ziprasidone combination compared with quetiapine combination for clinically significant response in mental state (> 50% reduction PANSS: 1 RCT, n = 63, RR 0.54, 95% CI 0.35 to 0.81, low quality evidence), global state (CGI ‐ Severity score: 1 RCT, n = 60, MD ‐0.70, 95% CI ‐1.18 to ‐0.22, low quality evidence) and mental state (PANSS total score: 1 RCT, n = 60, MD ‐12.30, 95% CI ‐22.43 to ‐2.17, low quality evidence). There was no effect for leaving the study early (1 RCT, n = 63, RR 0.52, CI 0.05 to 5.41, very low quality evidence).
Authors' conclusions
The reliability of results from this review is limited, evidence is of low or very low quality. Furthermore, due to the limited number of included studies, we were unable to undertake formal meta‐analyses. As a consequence, any conclusions drawn from these findings are based on single, small‐sized RCTs with high risk of type II error. Properly conducted and adequately powered RCTs are required. Future trialists should seek to measure patient‐important outcomes such as quality of life, as well as clinical response and adverse effects.
PICOs
Laički sažetak
Klozapin u kombinaciji s različitim antipsihoticima u liječenju shizofrenije otporne na postojeću terapiju
Dosadašnje spoznaje
Shizofrenija je teška duševna bolest koja uključuje različite simptome: halucinacije (događaje koji se čine stvarnim, ali su zapravo plod mašte), zablude (nerealna uvjerenja) i apatiju (bezvoljnost), koji imaju značajan utjecaj na kvalitetu života ljudi. Osnovnu terapiju čine lijekovi antipsihotici. Međutim, određeni broj ljudi koji boluje od shizofrenije ne reagira na antipsihotike (takozvana terapijska otpornost ili rezistencija). Upravo to predstavlja glavni izazov u daljem liječenju shizofrenije. Antipsihotik klozapin je učinkovit lijek za slučajeve koji su otporni na uobičajenu terapiju. Međutim, može izazvati neželjene učinke kao što su pospanost, vrtoglavica, glavobolja, tresavica i prekomjerno stvaranje sline (salivacija). Ozbiljniji neželjeni učinci su smanjenje broja bijelih krvnih stanica, što može dovesti do povećanog rizika od infekcija. Klozapin se često koristi u kombinaciji s drugim antipsihoticima u liječenju shizofrenije otporne na uobičajenu terapiju. U ovom Cochrane sustavnom pregledu istraživana je djelotvornost i sigurnost različitih kombinacija s klozapinom.
Karakteristike istraživanja
Pretraživanjem medicinske literature u kolovozu 2015. i siječnju 2016. godine pronašli smo pet kliničkih studija koje uključuju 309 odraslih osoba s dijagnosticiranom shizofrenijom ili sličnim bolestima koje su bile otporne na primijenjenu terapiju, ali su pokazale neku reakciju na klozapin. Studije su uspoređivale klozapin u kombinaciji s drugim antipsihoticima (kao što su haloperidol, aripiprazol, amisulprid, kvetiapin, sulpirid, ziprasidon i risperidon).
Ključni rezultati
Nije bilo moguće provesti zajedničku analizu svih rezultata jer se tih pet studija previše razlikovalo. Stoga su svi rezultati prikazani po pojedinačnim podacima o usporedbi dobivenim iz svake studije.
Kombinacija s aripiprazolom u usporedbi s kombinacijom s haloperidolom: nije bilo razlike u učinkovitosti te dvije terapijske kombinacije; međutim, kombinacija s aripiprazolom je izazivala manje neželjenih učinaka.
Kombinacija s amisulpridom u usporedbi s kombinacijom s kvetiapinom: kombinacija klozapina s amisulpridom je bila učinkovitija u liječenju shizofrenije nego kombinacija klozapina s kvetiapinom.
Kombinacija s risperidonom u usporedbi s kombinacijom sa sulpiridom: nije bilo razlike u kliničkim učincima između te dvije kombinacije.
Kombinacija s risperidonom u usporedbi s kombinacijom s ziprasidonom: nijedna od te dvije kombinacije nije pokazala prednost u odnosu na druge u poboljšanom djelovanju na simptome shizofrenije.
Kombinacija sa ziprasidonom u usporedbi s kombinacijom s kvetiapinom: kombinacija sa ziprasidonom je bila učinkovitija u poboljšanju kako mentalnoga tako i općeg stanja pacijenta u odnosu na kombinaciju s kvetiapinom.
Kvaliteta dokaza
Pouzdanost dokaza je upitna. Istraživanja su ocijenjena kao dokazi slabe ili vrlo slabe kvalitete. Bio je dostupan samo mali broj studija sa ograničenim brojem podataka. Podaci vezani za važne parametre kao što je kvaliteta života ili staranje o sebi nisu bili dostupni stoga nije bilo moguće napraviti čvrste zaključke. Za dalje istraživanje bili bi potrebni dokazi bolje kvalitete.
