Partial agonists and schizophrenia: theoretical developments for the development of mental health nursing

Partial agonists and schizophrenia: theoreticaldevelopments for the development of mentalhealth nursingM . J O N E S 1 r n d p r o ff , J . W H I T E 2 r n b s c & R . G R AY 3 r n p h d1Associate Director of Nursing, Surrey and Borders Partnership Foundation NHS Trust, and Visiting Professor ofMental Health Nursing University of Surrey, The Ridgewood Centre, Frimley, Surrey, 2Lecturer in Mental HealthNursing, University of Hull, Hull, and 3Professor of Research Related to Nursing and Deputy Associate Dean forResearch, Faculty of Health, University of East Anglia, Norwich, UK

JONES M., WHITE J. & GRAY R. (2009) Journal of Psychiatric and Mental HealthNursing 16, 409–415Partial agonists and schizophrenia: theoretical developments for the developmentof mental health nursing

People with schizophrenia have a significant impaired quality of life. The paper discusseshow partial agonists could improve the quality of life with people with schizophrenia incomparison with treatment with second generation antipsychotics. The paper provides aframework as to how mental health nurses can utilize the clinical benefits of partial agoniststhrough greater application of psychosocial interventions.

Keywords: mental health nursing, partial agonists, quality of life

Accepted for publication: 31 October 2008

Correspondence:

M. Jones

Mental Health Nursing University

of Surrey

The Ridgewood Centre

Frimley

Surrey

GU16 9QE

UK

E-mail: [email protected]

doi: 10.1111/j.1365-2850.2009.01373.x

Introduction

A large proportion of people with schizophrenia have sub-stantially impaired quality of life (QoL) (Strakowski et al.2005), specifically in terms of having purposeful employ-ment and vocational activity – in the UK only 8% of peopleare in employment. The advent of second-generationatypical antipsychotics, such as olanzapine and quetiapinebrought the prospect of an enhanced QoL for people withschizophrenia in comparison with the effects upon QoLof first-generation typical antipsychotics (such as halo-peridol and chlopromazine). This optimism associated withsecond-generation antipsychotics was reflected in govern-ment policy and healthcare recommendations to mentalhealth professionals and National Health Service (NHS)providers in the use of antipsychotics (National Institute ofClinical Excellence 2002b).

However, these assumptions were challenged when arecent randomized controlled trial found that no differ-ences occurred in the QoL in people with schizophrenia

whether they were prescribed first- or second-generationantipsychotic medication (Jones et al. 2006). The findingshave challenged our current assumptions in the literatureabout the effectiveness of second-generation antipsychoticsand the current UK national policy regarding the perceivedsuperiority of second-generation antipsychotic medication(National Institute of Clinical Excellence 2002a), whichhave major implications for mental health nursing (MHN)practice.

The theoretical framework underpinning third-generation antipsychotics – partial agonists, such as arip-iprazole – has provided a working hypothesis that mayprovide people, who use antipsychotic medications, withoptions to increase their QoL. The advent of partial ago-nists as treatment for schizophrenia has arrived in a fluidand exciting national mental health context. Changes in thelegal framework allowing mental health nurses to prescribe(Department of Health 2005), new ways of working withinthe NHS, facilitating cross fertilization of skills amongprofessionals (Department of Health 2001), health care

Journal of Psychiatric and Mental Health Nursing, 2009, 16, 409–415

© 2009 Blackwell Publishing 409

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driven by the consumer (Department of Health 2005) andchanges to the Mental Health Act (Department of Health2006a) have created the environment to be as revolution-ary for the role of the MHN and people with schizophreniaas much as when antipsychotics were first introduced in the1950s.

The purpose of this commentary paper is to outlinehow the third generation of antipsychotics – partial agonists– has the potential as an adjunct to skilled MHN care toincrease the opportunities for people with schizophrenia tomeet their life goals and aspirations in addition to exploringthe reasons why the increased social inclusion opportun-ities for people with schizophrenia treated with second-generation antipsychotics have been relatively modest.

Theoretical framework

Arguably people with schizophrenia experience the lowestQoL in the UK, where only 8% of people with schizo-phrenia will be in employment (Cook & Razzano 2000).People with schizophrenia have a reduced life expectancyof 15 years (Brown et al. 2000), with cardiovasculardisease (CVD) and suicide being the most prominentreasons for these unacceptably high mortality rates(Young 2005). The primary treatment for schizophrenia iswith antipsychotic medication (Taylor et al. 2007). Theefficacy in the treatment of positive symptoms is beyonddoubt (Taylor et al. 2007). In the 1950s antipsychotics,such as haloperidol and chlopromazine – (known astypical antipsychotics referred to as first-generationantipsychotics), transformed psychiatry for people withschizophrenia and resulted in symptom control, recoveryand discharge from the large Victorian asylums. How-ever, these antipsychotics have many unpleasant adverseeffects, the most prominent of which were being distress-ing and disabling movement disorders referred to as ExtraPyramidal Side Effects (EPSE), i.e. dystonia, parkinsonismand tardive dyskinesia (Taylor et al. 2007). The develop-ment of the second-generation antipsychotic medications,such as olanzapine, risperidone and qutiapine, was her-alded an opportunity to enhance both adherence withantipsychotic medication and the QoL of people withschizophrenia because of their much reduced propensityto EPSE (Jones et al. 2006).

The third generation of antipsychotics has taken thetreatment of schizophrenia one step further as they increasedopamine neurotransmission in the mesocortical dopaminepathway – the part of the brain that helps us think and planahead – and reduce dopamine neurotransmission in themesolimbic pathway – the part of the brain that helpsregulate emotion (White et al. 2007). Ideally, this therapyshould not exert an effect in both the nigrostriatal and

tuberoinfundibular dopamine pathway (Stahl 2001). Incomparison with the other atypical agents that act asantagonists of the D2 receptor completely blocking recep-tor activity and therefore exerting adverse effects, such asEPSE, adverse effects associated with increased levels ofprolactin and sedation, aripiprazole is a partial agonist andacts to stabilize dopamine levels in the brain (Kikuchi et al.1995, Pigott et al. 2003). A partial agonist can act as anagonist or an antagonist, depending on the concentrationof dopamine in the brain (Stahl 2001). At high dopaminelevels, a partial agonist will ‘block’ dopamine receptors,causing a reduced response and a lowering of dopaminelevels, thus reducing positive symptoms (White et al.2007). The use of partial agonists can result in adverseeffects, such as nausea, vomiting and agitation, particularlyin the initiation of partial agonists (Sullivan et al. 2007).

Evidence to support the framework

The latest research-assessing adherence with antipsychoticmedication conducted by Lieberman et al. (2005) demon-strated that rates of non-adherence with medication forpeople with schizophrenia might be much higher than con-ventionally thought. In the research of Lieberman et al.,75% discontinued their use of antipsychotics over a periodof 18 months, challenging the conventional view that 50%of people will discontinue taking antipsychotic medication.The research has raised questions about the role of mentalhealth professionals in using mental health medication inpeople with schizophrenia (Jones & Gray 2008). Furtherquestions about the role and purpose of medicationemerged from the Cost Utility of Antipsychotic Drugsreferred to as CUtLASS (Jones et al. 2006). The studyindicated that there was no difference on the patient’s QoLwhether they were prescribed first- or second-generationantipsychotic medication.

In a randomized controlled trial of the effect on QoL ofsecond- vs. first-generation antipsychotic drugs in schizo-phrenia, Jones et al. (2006) used a validated schizophrenia-specific measure, the Quality of Life Scale (Heinrichs et al.1984). They compared the QoL of 227 patients with schizo-phrenia after 1 year of treatment with either first-generationantipsychotics, such as perphanazine, or second-generationantipsychotics (such as olanzapine, risperidone, amilsuprideor quetiapine). They identified that no differences wereoccurring in the QoL at the conclusion of the research (Joneset al. 2006). Jones et al. (2006) predicted that the groupprescribed second-generation antipsychotics would experi-ence an improved QoL in comparison with people takingtypical antipsychotics. After 1 year no significant differencesin the QoL were occurring in people taking first- or second-generation antipsychotics.

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410 © 2009 Blackwell Publishing

In a separate naturalistic study, Hannssens et al. (2006)assessed the QoL in 555 patients treated for 26 weeks withthird-generation antipsychotic medication dopamine D2receptor partial agonists or standard of care. Data suggestthat patients treated with partial agonists showed a greaterimprovement in their QoL than standard care.

However, the research conducted by Jones et al. (2006),CUtLASS and Hannssens et al. (2006) has provided a theo-retical framework about why treatments with partial ago-nists – third-generation antipsychotics – may build capacityamong people with schizophrenia in the area of QoL andsocial inclusion. This would manifest itself in outcomes,such as increased vocational and employment activityamong people with schizophrenia.

Potential clinical implications

Why could the metabolic effects of second-generationantipsychotic medicines in people with schizophreniaincrease social exclusion?

A relatively common adverse event of the first- and second-generation antipsychotics is the effect on the body’s abilityto manage weight and the consequential increased risk ofdiabetes and CVD (Taylor et al. 2007). Products, such asolanzapine, seem to have a particular affinity to increasingweight, particularly in the first 8 weeks of treatment. Themechanism of action for this is not entirely understoodalthough it is thought that it is influenced by the antagonisticeffect of dopamine blockade (Tardieu et al. 2003). Despitethe reported risks of increased weight upon physical health,such as an heightened risk of developing type 2 diabetes andCVD, increased weight, which manifests in an increasedwaist circumference, is also associated with impacting uponself-esteem and QoL (Hofer et al. 2004, Olfson et al. 2005,Puschner et al. 2006, Faulkner et al. 2007).

How could the effects of second-generationantipsychotic medicines effect upon the endocrinesystem increase social exclusion?

A common side effect of some of the first- and second-generation antipsychotics, such as chlopromazine andrisperidone, is hyperprolactinaemia (Taylor et al. 2007).Prolactin is a hormone, and its primary bodily purpose isthe induction of lactation (Halbreich et al. 2003). Prolactinsecretion occurs in the tuberoinfundibular tract (Melmed1995). Dopamine exerts a prolactin-inhibiting response,therefore reducing dopamine transmission in the tuberoin-fundibular tract, which will result in an increase in levelsof prolactin (Melmed 1995). The immediate effect ofdrug-induced hyperprolactinaemia is on the sexual and

reproductive systems (Knegtering et al. 2000). However,other longer-term effects can occur – hyperprolactinaemiadecreases oestrogen and testosterone levels (Halbreichet al. 2003), and this may lead to osteoporosis. Sexualdysfunction and osteoporosis adverse effects associatedwith increased prolactin have also been associated with areduced QoL (Olfson et al. 2005).

How could the effects of second-generationantipsychotic medicines upon the histaminesystem increase social exclusion?

Histamine is involved in local immune responses as well asregulating physiological function in the gut and acting asa neurotransmitter (Stahl 2001). Many of antipsychoticsexert an antagonistic effect upon the histamine receptors; aconsequence of this is drowsiness (Stahl 2001). This issometimes referred to as somnolence (Taylor et al. 2007).Although this may be an initial helpful effect for the personwho is acutely unwell, once the symptoms associated withschizophrenia have subsided, drowsiness or somnolencewill decrease energy levels and act as a barrier to socialinclusion through inhibiting daytime activity (Strejilevichet al. 2005). This effect may further contribute to weightgain and placing an additional barrier to social inclusion.

How could the effects of second-generationantipsychotic medicines upon regulation ofmovement increase social exclusion?

A common side effect of the first-generation antipsychotics,although still occurring with a reduced propensity in thesecond-generation antipsychotics, is movement disorders(Taylor et al. 2007). This occurs because of dopamine block-age – a mechanism of action referred to as antagonism – inthe nigrostriatal dopamine pathway, the pathway in thebrain, which helps regulate movement (Stahl 2001). Move-ment disorders arising from adverse effects to antipsychoticsare associated with a reduced QoL (Puschner et al. 2006).

How could the effects of second-generationantipsychotic medicines upon the cholinergicsystem increase social exclusion?

Medication, which exerts an effect upon the cholinergicsystem, has been shown to have an effect upon cognition.Drachman (1977) identified that medicines, which exerts ananticholinergic effect, can produce cognitive deficits similarto those observed in the normal ageing process, such asshort-term memory loss and ability to sustain attention.Many of the atypical antipsychotics used in psychiatry exerta strong effect upon the cholinergic receptors (Stahl 2001).

Partial agonists and schizophrenia


Partial agonists a treatment approachto promote social inclusion – aworking hypothesis

What are the potential advantages of a mechanismof action of psychotropic medicine that enhancescognition and treats negative symptoms?

Schizophrenia is thought to occur primarily because of animbalance of dopamine (Stahl 2001). It is thought that toomuch dopamine transmission is occurring in the part of thebrain that regulates emotions – the Mesolimbic LimbicDopamine System – and too little in the part of the brainthat helps with cognition and thinking – the mesocorticaldopamine system. The role of all antipsychotics is to act asan antagonist and consequently block dopamine transmis-sion, as evidenced by there reported reduced effect intreating positive symptoms (White et al. 2007). The thirdgeneration of antipsychotics – partial agonists – maintain asteady level of receptor activation (Sullivan et al. 2007).Therefore, they reduce dopamine transmission where it istoo high and increase dopamine transmission where it istoo low (White et al. 2007). Theoretically this will result ina reduction of positive, negative and cognitive symptomsassociated with schizophrenia (Sullivan et al. 2007). Theimpact of negative symptoms and cognitive deflects onQoL is well described in the literature (Strejilevich et al.2005, Gur et al. 2006, Mittal et al. 2006). Hofer et al.(2004) has reported that cognitive underperformance isassociated with reduced occupational and social skills;hence, obtaining paid employment is extremely difficult.Hofer et al. (2004) also reports the impact of negativesymptoms upon QoL. The mechanism of action of partialagonists, which acts as a cognitive enhancer, may help toaddress some of these concerns.

What are the potential advantages of a mechanism ofaction with reduced propensity to adverse effects incomparison with second-generation antipsychotics?

Partial agonists have a low propensity to cause weight gain(Taylor et al. 2007). They have no affinity for blockingdopamine neurotransmission in the tuberoinfundibulardopamine pathway, therefore they do not cause increasedlevels of prolactin (Sullivan et al. 2007). They have noaffinity for blocking dopamine neurotransmission in thenigrostriatal dopamine pathway as a result that they gen-erally do not result in movement disorders from dopamineblockage in the nigrostriatal dopamine pathway (Whiteet al. 2007). They have minimal histamine affinity, there-fore minimal histamine antagonism occurs, so the persondoes not experience drowsiness (Jones & Gray 2008).

They also have reduced anticholinergic activity; therefore,reduced antagonism of the muscarinic receptors occurs, sothe drying of the mucous membranes, in addition to theheadaches, blurred vision and anxiety associated with anti-cholinergic side effects (Jones & Jones 2008). These effectsare the commonly reported effects, which people describeas distressing, disabling and impacting upon self-esteem,and they are all barriers to social inclusion.

How could treatment with partial agonists helpfacilitate the application of psychosocial intervention?

There has been an increasing emphasis on applying psy-chosocial intervention (PSI) driven on from a policy per-spective (National Institute of Clinical Excellence 2002a), aconsumer perspective (Department of Health 2005) and aprofessional perspective (Department of Health 2006b).Despite these drivers, their application into routine care inthe NHS is problematic (Fadden 1997). It is now nationalpolicy that all people with schizophrenia receive PSI, suchas Cognitive Behavioural Therapy as part of their care,the aim of which is to promote QoL. However, even whenwhole teams are trained in these approaches, their uptakeinto routine care remains disappointing (Fadden 1997). Arange of barriers have been discussed in the literatureexploring the reasons for this poor uptake, including cog-nitive difficulties associated with the illness, adverse effectsof treatment, the ability of the staff to apply PSI andsystemic barriers in the work setting (Brooker & Brabban2004). The common intrinsic barriers preventing theapplication of PSI are the cognitive difficulties that peoplewith schizophrenia experience and the adverse effects asso-ciated with antipsychotics, such as drowsiness, which workagainst the establishment of the therapeutic relation-ship (Sullivan et al. 2007). Symptoms associated with theillness, such as amotivation, alogia and effective blunting,are barriers to therapeutic relationship crucial to the imple-mentation of PSI (Turkington et al. 2004). The mechanismof action of partial agonists that results in a relativelybenign side effect profile could facilitate greater applicationof PSI, which in turn allows the likelihood of success ofsubsequent care packages to deliver social inclusion. First,these factors allow the development of the therapeutic rela-tionship in increasing participation in PSI packages of care(Turkington et al. 2004). The cognitive deficits associatedwith people who have schizophrenia have been cited asbarriers to application of PSI in people with schizophrenia(Heinrichs & Zakzanis 1998). By combining pharmaco-logical approaches that are cognitively enhancing withpsychological interventions, which attempt to enhance cog-nition, one would hypothesize that this will increase socialinclusion outcomes, such as purposeful employment oppor-

M. Jones et al.


tunities and focused daytime activity. The sedative effects ofantipsychotics have been cited as further barriers to theuptake of PSI, so the non-sedative effects of partial agonistscould further support uptake of PSI.

Ten per cent of people with schizophrenia will commitsuicide (Miles 1977, Fenton et al. 1997). Inevitably lowself-esteem and negative beliefs has a role in this (Perenyi &Forlano 2005), and as discussed weight gain and sexualside effects can affect self-esteem. A mechanism of actionthat does not cause these side effects may remove one of thebarriers preventing participation in activities, whichpromote social inclusion and build self-esteem, and allowfor facilitation of PSI.

It has been reported that negative symptoms inhibitthe application of PSI because of factors, such as avolitionand poor concentration. The role of partial agonists inincreasing dopamine activity in the mesocortical dopaminepathway theoretically improves levels of concentration,thus providing the MHN with an increased opportunity towork therapeutically in supporting people who use serviceswith their life goals and aspirations.

The removal of one of the primary barriers preventingthe application of PSI may have an enhanced effect onworker satisfaction and build practitioner self-esteem andincrease their capacity to provide care. These experiencesare thoughts and feelings associated with reduced stressand burnout (Maslach et al. 1996). This improvement intherapeutic attitudes will result in healthcare professionalsnot interpreting people who use services as contributing totheir own problems, and one could anticipate, help gener-ate a creative and innovative environment more conduciveto the application of PSI.

What could this mean for mental health nursing?

Mental health nursing by tradition delivers a holisticapproach to treatment. It prioritizes care to alleviate dis-tress, focusing upon restoring function and QoL. We wouldargue that partial agonists as a treatment could allowMHNs to reassert these key values as part of their practice,whether by building self-esteem associated with reducingthe risk of weight gain or by reducing risks of altered bodyimage through increased prolactin levels and restoringsexual drive, and helping the patient meet their life goalsthrough increase uptake of PSI.

Despite a growing evidence and national guidance,people with schizophrenia do not receive psychologicalinterventions as part of routine service provision (Brooker2001). This occurs despite large numbers of the workforcehaving now completed training in psychological interven-tions for people with schizophrenia (Brooker 2001). Theopportunities arising from the mechanism of action of

partial agonists may act as aid to facilitate the delivery of PSIto optimize recovery and prevent relapse, when previousmental health medicines may have acted as barriers. Theengagements of carers, where a patient is now being treatedwith a partial agonist, may introduce a different dynamicinto the application of family interventions. Where, as pre-viously, the patient may have been treated with an antipsy-chotic with a sedating effect, the practitioner practicingfamily interventions will need to prepare themselves and thefamily to a scenario where the patient may now be morealert and animated in the family meetings.

The MHN will need to develop models of care that viewQoL as a combination of the subjective experience thatpeople have of their illness and the helpful and unhelpful oftreatments that together contribute to QoL. The aim ofcare will be to minimize cognition and negative symptomswhile minimizing adverse effects. This will require theMHN to combine psychological approaches, such asadherence therapy, the ability to provide the patientinformed choice of pharmacological interventions and thedelivery of social interventions (such as education, skillstraining and lifelong learning), all aimed at creating andmaintaining independence.

The MHN will need to have advanced technical knowl-edge of antipsychotics, their mechanism of action, a skilfulrepertoire of nursing interventions to minimize theiradverse risks and a clear understanding of safe strategies inswitching antipsychotics. This knowledge and expertiseshould be used to support patients make choices abouttheir use of medicine that best supports their goals andaspirations.

Implications for researchers

The paper has raised a series of questions for further evalu-ation. The two most recent studies exploring the impactof the second- and third-generation antipsychotics uponsocial inclusion have helped provide a tentative theoreticalframework, which argues that partial agonist in combina-tion with skilled MHN may increase the opportunities forsocial inclusion for some people with schizophrenia in com-parison with second-generation antipsychotics. Carefullydesigned controlled studies are now required to attempt toprovide evidence to support or disprove this theory.

Key research questions to consider:1. What is the uptake and perceived difficulties among

MHNs of applying PSI with people who have beenprescribed partial agonists in comparison with otherfirst- and second-generation antipsychotics?

2. What is the effectiveness of combining PSI with differentantipsychotics in helping people obtain purposefulemployment?



3. A qualitative research assessing people’s experiences ofusing different antipsychotics and their views as to howantipsychotics enable them to meet their life goals.

4. A qualitative assessment of what is meant by socialinclusion and how social inclusion can be enhancedfrom a professional, patient and carer perspective.

5. Does use of different antipsychotics impact upon MHNwell-being?

Conclusion

A large proportion of people with schizophrenia have asignificantly impaired QoL. There are many reasons forthis: first, the manifestation of the illness, in particular,cognitive deficits associated with schizophrenia; second,the adverse effects of the treatments we use for schizophre-nia act as a further barrier to social inclusion; third, thedifficulties, which MHN find in applying evidence-basedcare and treatments that support social inclusion. Finallythe attitudes and the therapeutic optimism of professionals,who provide care for people with schizophrenia, may alsoimpede recovery.

The introduction of partial agonists has provided a theo-retical framework that may enhance the QoL of people withschizophrenia. This occurs through a reduction in adverseeffects and a mechanism of action, which addresses theproblem of cognitive deficits that people with schizophreniaexperience. These in turn may facilitate greater applicationof evidence-based care, such as PSI. A consequence of thismay be an increase in therapeutic optimism of the MHN,innovation and creativity in the work place associated withenhanced worker satisfaction.

The science of partial agonists may provide MHNs withan opportunity to practise the art of their craft. An excitingtime for the profession looms.

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Partial agonists and schizophrenia: theoretical developments for the development of mental health nursing