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Psychiatria Danubina, 2014; Vol. 26, Suppl. 1, pp 315–321 Conference paper Medicinska naklada - Zagreb, Croatia COMBINING ANTIPSYCHOTICS; IS THIS STRATEGY USEFUL?
Jill Christy1,2, David Burnside1,3 & Mark Agius4,5,6
1School of Clinical Medicine, University of Cambridge, Cambridge, UK 2St Catharine's College University of Cambridge, Cambridge, UK 3Robinson College University of Cambridge, Cambridge, UK 4Clare College University of Cambridge, Cambridge, UK 5Department of Psychiatry University of Cambridge, Cambridge, UK 6South Essex Partnership University Foundation Trust, Cambridge, UK Antipsychotic drugs are commonly combined in psychiatric practice in an attempt to treat schizophrenia. Such practice is widespread, despite the lack of explicit endorsement by many of the main regulatory bodies. There are varying rationales behindcombining these potent drugs-either to augment the effect of a drug whose action alone is inadequate for patients with treatmentresistant schizophrenia (TRS), or to improve the side effects seen due to treatment. Augmentations are most frequently observed with clozapine, a drug reserved for use when other antipsychotic medications have failed. Several drugs have been chosen as adjuvants, including aripiprazole, sulpiride, amisulpiride and risperidone. A small number of RCTs (randomized controlled trials) have beenperformed but, despite this data and numerous case reports showing positive changes in symptomatology, Cochrane reviews of available studies have been unable to definitively confirm the efficacy of these combinations, frequently citing the need for larger,longer term, prospective studies.Evidence for benefits of combination therapy on side effects is also inadequate. Some RCTs and case series have shown they can positively alter side effects due to drugs such as clozapine, e.g. metabolic side effects. However, despite many of the combinations being relatively well tolerated, there is some evidence they can cause adverse effects of their own. Moreevidence is essential as, on the current data alone, it is not possible to make a firm recommendation on the efficacy and safety of antipsychotic combinations. In addition it is vital that the importance of a fair trial of monotherapy at adequate dosages is reinforced to clinicians, so that patients are not put onto these relatively unknown treatment strategies unnecessarily. Key words: antipsychotic – combination – augmentation – clozapine – aripiprazole – amisulpride – sulpiride – risperidone –
schizophrenia - treatment-resistant
assess the combination of antipsychotics, one would need to assess the effect of each drug separately and Combinations of antipsychotic drugs are commonly then determine the degree to which each drug counter- seen in clinical practice for treatment of schizophrenia, balances or modifies the other. Furthermore, one would with 15% of out-patients and 50% of hospitalised need to measure any adverse or unexpected effects that patients receiving polytherapy(Freudenreich and Goff, arise from combining multiple drugs, each with varying 2002). However this practice is not explicitly endorsed modes of action. This is not feasible to perform in full in by the guidelines of NICE on schizophrenia (NICE, clinical trials and as such the main investigation that can 2014), by the World Federation of Societies of Bio- be undertaken is to compare the effect of a combination logical Psychiatry (Falkai et al. 2005), nor the British of treatments to each treatment separately. This is far Association for Psychopharmacology (Barnes and from ideal but currently, along with case studies, Psychopharmacology 2011). NICE states that regular constitutes the extent of evidence available to determine combined antipsychotic medication should not be whether combining antipsychotics is an effective and initiated, except for short periods of time, such as when changing medications (NICE 2014). Several reasons are proposed for the combination of antipsychotics. Firstly, AUGMENTATION STRATEGIES
another antipsychotic may be prescribed if the patient is treatment resistant or is having a limited or unsatis- One justification for combining antipsychotics is for factory response to monotherapy, in order to augment augmentation purposes when monotherapy efficacy has the drug's action. Alternatively, other antipsychotics been limited, or when the disease remains treatment may be added to counteract various side effects of resistant. The rationale behind the choice of drug com- effective antipsychotics, which may be impacting binations may not be clear (Barnes and Psychopharma- patient compliance or may be indicating cessation of cology 2011) but NICE only suggests choosing a drug therapy. The mechanistic rationale behind how these that does not exacerbate existing side effects of the processes occur is not transparent and as such one current antipsychotic (NICE 2014). There have been would anticipate a strong evidence base to justify the various suggestions as to why an augmentation strategy utilisation of polytherapy. However, in order to fully might be successful. One proposal was that a better Jill Christy, David Burnside & Mark Agius: COMBINING ANTIPSYCHOTICS; IS THIS STRATEGY USEFUL? Psychiatria Danubina, 2014; Vol. 26, Suppl. 1, pp 315–321 outcome might arise through an increased serum level matology improved, whilst major side effects were of the original drug (Tyson et al. 1995). This theory absent on aripiprazole-clozapine combination therapy however could not be validated in a study undertaken by (Mossaheb et al. 2010). Furthermore, a retrospective (Henderson & Goff 1996). Other guidance suggests the study examined notes of adolescents on an aripiprazole- selection of an augmenting antipsychotic which has a clozapine combination regime and found that the mean complementary receptor profile, e.g. a D2 dopamine clinical global impression scores improved significantly, receptor blocker, which pharmacologically rationalises suggesting such a therapy may be effective in both their use (Genc et al. 2007, Kontaxakis et al. 2005). adolescents and adults (Bachmann et al. 2009). A 2008 RCT found that aripiprazole-clozapine com- Augmentation of Clozapine
pared to placebo did not significantly affect total symptomatology in schizophrenia, but the negative In cases where the response to antipsychotic treat- symptom improvement was significantly greater than ment is unsatisfactory, so called ‘treatment resistant placebo in secondary analysis (Chang et al. 2008), schizophrenia' (TRS), clozapine is often chosen. How- whilst (Muscatello et al. 2011) described the results of a ever even on this drug reserved for TRS, 40-70% of 24-week double-blind, randomized, placebo controlled patients will not improve to the desired level (Mossaheb trial which found beneficial effects of combination & Kaufmann 2012). Augmentation of clozapine is one therapy on positive and general symptomatology in a of the most studied combinations of psychotropic sample of TRS patients. One group (Ziegenbein et al. medication. Various antipsychotics have been added to 2006) found that in 11 TRS patients on an aripiprazole- clozapine to examine their effect, to varying degrees of clozapine combination, the mean BPRS score was signi- success, with several randomised double-blind, placebo- ficantly reduced in seven patients over 3 months of controlled trials carried out. Commonly antipsychotics treatment, with the therapy being well tolerated and such as risperidone, amisulpride, sulpiride, haloperidol allowing for a significant reduction in daily clozapine and aripiprazole are used as the adjuvant. dose. This may be of benefit in treating so called ‘treatment-intolerant' patients, reducing the rates of Aripiprazole and clozapine
clozapine side effects such as agranulocytosis, sedation, weight gain, sialorrhoea, and enuresis. Other papers In recent research, aripiprazole has commonly been have reported similar dose reductions, such as (Englisch investigated as an adjuvant to clozapine monotherapy, & Zink 2008) who showed that a mean dosage of 20.5 presumably due to its favourable metabolic side effect mg/day aripiprazole achieved clinical improvement of profile. Data for the efficacy of such a strategy provides psychotic symptoms whilst simultaneously facilitating a conflicting results. In a 2013 randomised superiority dose reduction of clozapine from 476.7 to 425.1 mg/day. study, augmentation with aripiprazole was compared to Taken together, these trials suggest that a combi- haloperidol (Cipriani et al. 2013). They concluded that nation therapy may have some additional efficacy in the only significant difference between haloperidol and treating schizophrenic symptoms, although larger scale aripiprazole augmentation came in tolerability- aripipra- prospective studies are needed. zole decreased the tolerability score significantly more than haloperidol. Both augmentation strategies were of Effect of clozapine and aripiprazole
similar efficacy. This study is somewhat limited due to its small size and lack of a placebo control, such that it combination on side effects
is impossible to conclude if such augmentation impro- Schizophrenics have a significantly increased risk of ves tolerability vs clozapine monotherapy. However, cardiometabolic disease leading to morbidity and similar improvements can be seen in other trials, such as mortality. Clozapine is often used in TRS, due to its that published by (Barbui et al. 2011). They showed that apparent superior efficacy when compared to other the 3-month Liverpool University Neuroleptic Side atypicals. However, it is reserved for these treatment Effect Rating Scale total score was significantly higher resistant cases due to its unfavourable side effect in those taking aripiprazole than haloperidol, leading to profile, with substantial evidence that it worsens cardio- their conclusion that improved perception of adverse vascular risk factors including weight gain, dyslipi- effects was seen with aripiprazole. Taken together, these daemia, hypertension, and diabetes. These metabolic studies suggest that combination therapy may be risks are believed to be at least partly due to its strong beneficial in terms of side effect profiles, rather than blockade of 5HT2C and Histamine H1 receptors symptom control. (Kroeze et al. 2003) and stimulation of hypothalamic There is, however, emerging evidence that such com- AMPK (adenosine monophosphate activated protein bination therapies may also improve patients' sympto- kinase), an enzyme that reverses the effects of leptin. matology. A retrospective case series of aripiprazole (Kim et al. 2007). Unlike clozapine, aripiprazole has no augmentation in clozapine-treatment resistant schizo- histaminergic activity, and is a 5HT2C agonist (Herrick- phrenia patients found significant improvements in Davis et al. 2000). Moreover, it has some agonist psychopathology, functional outcome and metabolic activity at 5HT1A receptors, believed to lower blood indices after 6 weeks (De Risio et al. 2011). Four cases glucose levels. Monotherapy with aripiprazole often has were reported in whom positive and negative sympto- minimal impact on a patient's metabolic profile, yet Jill Christy, David Burnside & Mark Agius: COMBINING ANTIPSYCHOTICS; IS THIS STRATEGY USEFUL? Psychiatria Danubina, 2014; Vol. 26, Suppl. 1, pp 315–321 lacks the efficacy of clozapine. Therefore, there is a combination and placebo groups were not statistically mechanistic reasoning behind augmenting clozapine significant, and no subjects withdrew from the trial as a with aripiprazole- the effects of aripiprazole on 5HT2C result of them, they should be borne in mind whilst and 5HT1A receptors may in fact protect against the deciding on initiating a patient on such combination diabetes, weight gain, and dyslipideamia induced by therapies. There have also been rare cases of psychosis clozapine. Within the literature, there is some evidence exacerbation following aripiprazole initiation (Mossaheb of such beneficial effects. A 2013 randomised, double & Kaufmann 2012) which, although rare, are a concern. blind, placebo controlled study (Fan et al. 2013) Taken as a whole, trial data shows positive effects of examined the metabolic effects of adjunctive aripipra- this combination on psychopathology and, to some zole therapy in clozapine-treated schizophrenics over an extent, negative symptoms. Moreover, the combination 8 week period. Subjects received either 15mg/day provides the possibility of reducing a patient's daily aripiprazole or placebo in addition to their standard clozapine dosage. However, the precise size of these clozapine, and the impact on metabolism was compared benefits on symptomatology is unclear. Perhaps the via glucose tolerance test, MR spectroscopy, and DXA more significant beneficial effects come from modifi- scans before and after the trial. The results show a cation of treatment side effects, with better metabolic significant improvement in insulin sensitivity, reduced outcomes. However, other side effects, such as aka- LDL and reduced lean and total body mass. Despite the thesia and hypersalivation, are repeatedly reported. limitations of the study, including the small number of From current trial data, it is not possible to draw any participants (n=30) and short study period, it does firm conclusions regarding tolerability and long-term appear to lend support to such an augmentation strategy, safety of an aripiprazole-clozapine combination. How- with similar benefits found in other papers (Chang et al. ever, the promise of the aripiprazole-clozipine treatment 2008). For example, a randomised, double-blind, pla- regime warrants further investigation. cebo controlled trial of a stable dose of clozapine augmented with 5-15mg/day of aripiprazole, was Amisulpride and clozapine
performed with patients who were not adequately controlled on clozapine for 3 months or more and had Another frequently used adjuvant to clozapine is experienced weight gain of 2.5kg or more whilst taking amisulpride. Since amisulpride has high-affinity binding clozapine (Fleischhacker et al. 2010). The authors found to D3/D2 dopamine receptors, this dopamine blockade that weight loss from baseline was significantly diffe- can rationally be added to the relatively non-selective rent in patients on aripirazole vs placebo, and factors clozapine. Various publications support this rationale, such as BMI and waist circumference were also with some evidence of improved symptomatology, reduced. Reductions in total and low density lipoprotein along with substantial improvements in side effects. levels were also greater in the aripiprazole group over (Cook & Hoogenboom 2004) describe 6 cases where placebo, however positive and negative symptoms were patients on clozapine monotherapy have their treatment not significantly affected. These studies therefore lend augmented with amisulpride. On monotherapy, all 6 support to the rationale of improving side effect patients were suffering from unwanted effects, including hypersalivation, weight gain, and sedation. Another potential benefit of combination therapy has However, the regime change allowed for a significant been highlighted by a recent case report (Lee and Kim, clozapine dose reduction, leading to fewer side effects, 2010). Clozapine monotherapy can produce urinary without a recurrence of positive symptoms. In another system side effects, particularly enuresis, in 6-43% of case series of 15 patients, 6 had a major improvement of patients (Lin et al. 1999). This can lead to non-com- their positive and negative symptoms which, until pliance, and impact on quality of life. However, Lee et augmentation, had been treatment resistant, whilst a al. report on 2 cases where combination treatment with further 8 had marked improvement in symptomatology. aripiprazole and clozapine effectively treated clozapine- Again, a reduction in clozapine dose was possible, induced enuresis. Larger, more systematic studies are leading to significantly fewer side effects (Zink et al. required to provide confirmation of this effect, which 2004). In an open, non-randomized study of amisulpride may be a key benefit of combination therapy in such augmentation of clozapine, (Munro et al. 2004) found no worsening of drug effects over a 6 month period, Despite the reported benefits on major metabolic other than a large increase in serum prolactin. They side effects and enuresis, such combination therapies are noted no clinical manifestations of the elevated not without their problems. In the aforementioned paper prolactin, possibly as most of the patients were male. (Fan et al. 2013), certain side effects were reported in After 6 months, this prolactin level was falling again, in more than 5% of the aripiprazole-clozapine combination line with previous data showing that prolactin levels group, and these occurred at least twice as commonly as decrease after an initial spike (Schlosser et al. 2002), in the placebo controls. These side effects include over- and there was a very low drop-out rate amongst arousal, drowsiness, headache, back pain, itching, nasal participants. Later, a randomised, double-blind, placebo congestion, hypersalivation, stomach discomfort, nau- controlled trial was carried out to evaluate amisulpride sea, and vomiting. Although these differences between augmentation of clozapine. The authors noted Jill Christy, David Burnside & Mark Agius: COMBINING ANTIPSYCHOTICS; IS THIS STRATEGY USEFUL? Psychiatria Danubina, 2014; Vol. 26, Suppl. 1, pp 315–321 improvements only in the scores of secondary outcome rhoea). Additionally, there is some indication from the measures such as GAF, CGI and MADRS, with primary trials that patients experience less weight gain and outcomes (BPRS) failing to show significant improve- hypersalivation versus clozapine monotherapy, which ment. The study was limited due to its small sample size would be of great benefit. However, the data for such (n=15), hence it was concluded that whilst such therapy side effects is so small in size that much larger studies may lead to improvements in overall outcome for TRS are needed before any definitive conclusions can be patients, a larger study with more power would benefit the analysis (Assion et al. 2008). A recent study suggests that amisulpride-clozapine Risperidone and clozapine
combination therapy may have benefits beyond impro-ving symptomatology and side effects. (Hotham et al. In addition to earlier open studies and case reports, a 2013) found that in a subgroup of 6 violent schizo- 2005 double-blind RCT showed significantly superior phrenics who responded poorly to clozapine, addition of improvement of positive, negative and total psycho- amisulpiride led to significant reduction in aggression pathology when adding risperidone of up to 6 mg/day to whilst leaving metabolic parameters and side effects clozapine (mean dose 400 mg/day) (Josiassen et al. largely unchanged. Such a strategy warrants further 2005). In contrast to these results another RCT revealed a significantly inferior improvement of positive symp-toms by adding risperidone compared to placebo (Anil Taken together, the above data implies a positive Yagcioglu et al. 2005). effect of combination on psychopathology, whilst allo-wing for a simultaneous reduction in clozapine dosage. However, unlike the aripiprazole-clozapine combina- COMPARING STRATEGIES
tion, there seems to be no convincing evidence for a reduction in the metabolic side effects associated with Many other drugs are commonly added to clozapine clozapine above and beyond those due purely to a dose- to increase its efficacy and perhaps to reduce side- effects including risperidone, haloperidol, quetiapine and olanzapine. However, most of the work done to investigate has focused on the above drugs. Despite the Sulpiride and clozapine
variability in the findings of each trial and case series, Whilst much of the current literature focuses on and the frequent conclusion that further, larger studies aripiprazole or amisulpride augmentation of clozapine, need to be done to truly expose any efficacy and reveal there have been numerous studies into using other any adverse effects, it is also of importance to determine adjuvant drugs. While combining clozapine with chlor- whether one combination of drugs is preferable to promazine revealed no benefit (Potter et al. 1989), adding sulpiride to clozapine led to a more than 20% In 2009, a Cochrane review of 3 small RCTs which decrease in psychopathology (BPRS total score) and evaluated the combination of risperidone, sulpiride, superior improvement compared to placebo (Shiloh et ziprasidone or quetiapine with clozapine was performed al. 1997). The use of sulpiride, a selective D2 and D3 (Cipriani et al. 2009). They were unable to reach a antagonist, can be rationalized mechanistically as one conclusion as to whether one augmentation strategy was would anticipate an enhancement of clozapine's D2 more effective than another, in part due to the receptor blockade. A double blind, placebo controlled limitations of study design and enactment. Conversely, study of 28 people found that the group treated with in a single-blind randomised study comparing clozpine- clozapine augmented by sulpiride had significant amisulpride and clozapine-quetiapine combinations, as improvements in positive and negative symptoms, early as third week of treatment, scoring revealed that greater than those seen in the placebo group, leading the improvement was significantly greater with amisulpride authors to conclude that a subgroup of patients with than with quetiapine. This led to the authors concluding chronic schizophrenia may benefit greatly from this that amisulpride is effective and well-tolerated (Genc et augmentation strategy (Shiloh et al. 1997). In a al. 2007). As previously mentioned, in a similar compa- Cochrane review, 3 short term trials and one long-term rison of aripiprazole and haloperidol augmentation of trial in patients either with TRS or with schizophrenia clozapine, aripiprazole was considered to be better with distinct negative symptoms were reviewed. The tolerated but there was no significant difference in conclusions determined that the combination of efficacy (Cipriani et al. 2013). It appears that there is no sulpiride plus clozapine was more effective than outstanding preferred treatment that has been clozapine alone but that further data would be required demonstrated to be efficacious over other combination to make firm conclusions (Wang et al. 2010). therapies. This makes the decisions to choose an The side effects associated with such a combination augmentation therapy if a practitioner chooses to do so, are also addressed in the Cochrane review, with reports much harder, as the evidence supporting the combi- of extra-pyramidal movement disorders and an increa- nation of treatments is lacking power, and there is little sed prolactin, although there were no reports of any clear guidance from previous studies as to which clinical features associated with this (e.g. galactor- combination is better tolerated and most efficacious. Jill Christy, David Burnside & Mark Agius: COMBINING ANTIPSYCHOTICS; IS THIS STRATEGY USEFUL? Psychiatria Danubina, 2014; Vol. 26, Suppl. 1, pp 315–321 Augmentation of other antipsychotics
last explanation would warrant long term continuation of combination therapy. Clozapine is not the only monotherapy on which There are also issues surrounding long-term safety augmenting strategies have been attempted, although it of such combination therapies. By giving two drugs, is the one on which most trials and case series have there is clearly a greater risk of drug-drug interactions, been done, due to its frequent selection in TRS cases. which may have long term effects on morbidity and Olanzapine is another atypical antipsychotic which has mortality not yet obvious from the limited, relatively been augmented. In a case series, augmentation of short term trial data available. The addition of a second olanzapine with sulpiride improved positive and drug may also impact on patient adherence due to negative symptoms (Raskin et al. 2000). However, a increased treatment complexity. randomised controlled study of patients with TRS concluded that sulpiride augmentation of olanzapine did not benefit positive or negative symptoms but improved CONCLUSION
depressive symptoms. This trial contained a small sample size and the therapies were studied over 8 weeks Current evidence does not allow for any (Kotler et al. 2004). In addition, clozapine can be used endorsement of antipsychotic polypharmacy in routine to augment other psychotropic medications. For exam- practice. However, it is also not possible to confidently ple, (Hung & Chen 2009) reported the case of a patient state that such a strategy would never have a reasonable for whom administration of aripiprazole and risperidone risk-benefit balance for a given patient. Thus, combined respectively induced severe extra-pyramidal symptoms, antipsychotics should be prescribed on an individual but a combination of clozapine and aripiprazole resulted basis, as a closely monitored, time-limited trial, consi- in control of symptoms and reduced EPS. Obviously dered only after a lack of response to several adequate this is a single case study, making it impossible to draw trials of antipsychotic monotherapy, including cloza- any conclusions. However, it does point to another pine. Future studies will undoubtedly shed more light on potential benefit of combination therapies. Each combi- the potential benefits of combination therapy, and nation will require thorough investigation, as results for hopefully open up new avenues of treatment for patients one combination are not transferable to others due to the suffering from not only their illness, but the effects of vast array of receptor binding profiles. essential treatment. Currently available evidence for antipsychotic poly- Conflict of interest: None to declare.
pharmacy is insufficient to make definitive conclusions regarding efficacy and safety. There are multiple case reports, open trials, and even RCTs, yet they all suffer from issues regarding study numbers, power, and References
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Correspondence: Mark Agius, MD SEPT at Weller Wing, Bedford Hospital Bedford, Bedfordshire, MK42 9DJ, UK E-mail: [email protected]

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