Ryota Ataniya

Juntendo Psychiatric Research Institute,Juntendo University,Tokyo,Japan

Abstract

Key words:schizophrenia;antipsychotics,high dose;relapse;dopamine;pharmacotherapy

DRUG THERAPY AND RELAPSE IN PATIENTS WITH SCHIZOPHRENIA

The treatment goal for patients with schizophrenia during the stable phase is the prevention of relapse and improvement in quality of life and functions.Relapse is not a rare event,and it often occurs as a part of the natural course of illness.Relapse suddenly occurs without prior symptoms in most cases.Psychotic symptoms similar to those previously experienced by patient are noted after a patient experiences relapse.The cost of treatment for patients who relapse is three times higher than that of patients who do not.Relapse itself becomes a predictor of a subsequent relapse (Ascher-Svanum et al.,2010).Poor compliance to antipsychotic therapy has a substantial effect on relapse;thus,good compliance to antipsychotic drugs plays a major role in the prevention of relapse.Maintenance therapy with antipsychotics may decrease the incidence rate of relapse to approximately 30% or lower within 1 year (Lehman et al.,2004).However,without such therapy,the rate increases to 60-70% and to 90% within 2 years.The incidence rate of relapse within 1 year can reach as high as 46% even in patients who receive antipsychotic therapy (Lehman et al.,2004).

When patients with good compliance to antipsychotic treatments relapse,drug therapy options include a switch to another antipsychotic,increased dose of the currently administered antipsychotic,or addition of adjuvant therapy.For patients who do not achieve remission after such therapy,another oral antipsychotic drug may be included in the treatment regimen,which is the last alternative (Kane et al.,2003).An increased dose of antipsychotics results in the frequent onset of adverse events as well as poor tolerability to oral medications.Administration of an increased dose of antipsychotics for worsening symptoms may not always have beneficial effects;moreover,there is a positive correlation between high dose of antipsychotics and increased incidence of adverse events.

SEARCH STRATEGY

An electronic search of the Medline database for literature describing patients with schizophrenia who relapse while receiving high-dose antipsychotic therapy from 1989 to 2018 was performed using the following conditions:schizophrenia AND antipsychotic therapy.The results were further screened by title and abstract to patients.

DEFINITION OF RELAPSE

According to a meta-analysis of schizophrenia (Olivares et al.,2013),hospitalization was the most commonly used term to define relapse,followed by the Positive and Negative Syndrome Scale,particularly for the score of symptom severity and worsening and re-appearance of positive symptoms of the disease.The following terms were also used to define relapse in clinical trials:violent behavior resulting in clinically significant injury to another person or property damage,deliberate self-harm,and suicidal or homicidal ideation.

A HALVED DOSE OF ANTIPSYCHOTICS IN PATIENTS WITH SCHIZOPHRENIA WHO RELAPSE WHILE RECEIVING HIGH-DOSE ANTIPSYCHOTIC THERAPY

Patients who are on high-dose antipsychotic therapy are more likely to receive treatment in a hospital where clozapine treatment is not available.And they would have had little or no responses to previous monotherapy using several antipsychotics.In fact,there is no other drug treatment alternative other than hospitalization for relapsed patients with high-dose antipsychotic treatment,they often need to be hospitalized for safety.Hospitalization is one of the major drivers of healthcare costs,contributing up to two-thirds of the total direct costs of treating patients with schizophrenia (Lafeuille et al.,2013).The restraints used to minimize dangerous behavior increase the risk of pulmonary embolism,neuroparalysis,and gastrointestinal bleeding.In addition,relapse or prolonged relapse phase results in impairment in cognitive and daily life function and decreased quality of life.Treatment with a halved dose of antipsychotics is costless and no risk for restraint and it reduces the duration of the relapse phase,minimizes the deterioration of cognitive and daily life function and quality of life.

The target dosages are approximately 1000 mg/d and halved dose from the current dosage for patients who receive chlorpromazine-equivalent of an antipsychotic drug with a dose of ≤ 2000 mg/d and ≥ 2000 mg/d,respectively.An abrupt reduction to halved-dose antipsychotic treatment might induce antipsychotic withdrawal symptoms.However,patients who are receiving high-dose antipsychotic therapy cause several adverse effects,such as extrapyramidal symptoms,including dystonia and dyskinesia resulting from excessive blockade of dopamine receptor,as well as cardiovascular and gastrointestinal symptoms,due to such therapy,and a decrease in antipsychotic dose will lessen these adverse effects,resulting in compensation for the withdrawal symptoms.A halved dose compared with high-dose antipsychotic therapy might lessen the excessive blockade of dopamine receptors,thereby resulting in the optimization of dopamine levels.A meta-analysis by Leucht et al.(2012) has indicated that the frequency of withdrawal dyskinesia was higher with the abrupt discontinuation of antipsychotics compared with discontinuation after tapering the dose for a certain period of time;however,the incidence of other adverse events was similar.The administration of antipsychotics was discontinued in their study.However,in the present study,the dose of antipsychotic drugs is halved,not discontinued;hence the risk of developing adverse events is considerably low.The meta-analysis demonstrated the lack of relationship between abrupt discontinuation and an increased risk of relapse (Gilbert et al.,1995;Leucht et al.,2012),which indicated that withdrawal symptoms do not lead to relapse (Emsley et al.,2018).Therefore,a halved dose of antipsychotics is less likely to worsen symptoms.

CAUSES OF RELAPSE AND RELATIONSHIP BETWEEN RELAPSE AND DOPAMINE

The causes of relapse include increased cortisol levels owing to social,psychological,or physiological stress,abnormalities in glutamatergic transmission,immunodeficiency,inflammation,and a decrease in neurotrophin levels such as brain-derived neurotrophic factor,which lead to an increase in dopamine levels and induce psychotic symptoms.This phenomenon is referred to as the final common pathway hypothesis (Howes and Kapur,2009),which explains that dopamine perturbation eventually causes relapse and appears as clinical symptoms.Even one dose of amphetamine might cause dopamine perturbation,which results in the occurrence of psychotic symptoms that persist for a certain period.

The capacities of presynaptic dopamine synthesis and release of dopamine in the striatum are enhanced in patients with schizophrenia (Kambeitz et al.,2014;Horga et al.,2016;Howes et al.,2017;Weinstein et al.,2017).During the worsening phase of psychotic symptoms and the relapse phase,the release of dopamine neuron increases,and the level of extracellular dopamine level is elevated (Weinberger and Laruelle,2002;Howes et al.,2012;Fusar-Poli and Meyer-Lindenberg,2013).Administration of amphetamine causes the inactivation of dopamine active transporter and increase in the release of dopamine from the endoplasmic reticulum.In patients with schizophrenia,dopaminerelease by dopamine agonists is correlated with the worsening severity of positive symptoms (Laruelle et al.,1999;Howes et al.,2012).dopamine agonists worsen positive symptoms in these patients (Laruelle et al.,1996),whereas antipsychotic drugs have dopamine D2 receptor blocking effect,and dopamine D2 receptor blockade exerts antipsychotic action (Kapur and Remington,2001;Kapur,2003).Hypodopaminergic state is associated with apathy and anhedonia and in that state,external stimuli that are important to the organism are hardly or not motivated (Juckel,2016).

DOPAMINE FUNCTIONS AND POSITIVE SYMPTOMS

Dopamine neurons fire tonically and phasically in the striatum,and phasic depolarization causes considerable changes in dopamine levels in downstream structures.Phasic dopamine responses result from sensory cues in reward and rewardrelated systems,which are measured by nuclear medicine examination,fMRI,and electrophysiology examinations.In the reward system,dopamine signal represents prediction error,i.e.,the difference between the expected and received reward (Schultz,2013);thus,prediction error is an important teaching signal for animals to learn the relationship between stimuli and results.Dopamine signal is activated by motivational task,it encodes motivational values that are not only positive motivation but also inhibited by aversive events and plays a role of motivational control by dopamine (Bromberg-Martin et al.,2010).The activation of dopamine in the striatum caused by incentive tasks is correlated with the release of dopamine (Schott et al.,2008),and levodopa and antipsychotics control the behavior related to reward (Pessiglione et al.,2006;Rutledge et al.,2009).

Patients with schizophrenia show abnormal activation in the ventral striatum to reward prediction error (Murray et al.,2008),and ventral striatal activation during reward anticipation is correlated with positive symptoms (Esslinger et al.,2012;Nielsen et al.,2012).In patients with schizophrenia,increased behavioral,autonomic and neural responses for neutral stimuli in incentive tasks are correlated with positive symptoms (Jensen et al.,2008;Murray et al.,2008;Romaniuk et al.,2010;Diaconescu et al.,2011),and midbrain activation for neutral cues was associated with delusions (Murray et al.,2008;Romaniuk et al.,2010).

The aberrant salience hypothesis proposes that Patients with schizophrenia may attribute salience to otherwise neutral environmental stimuli (Kapur,2003;Howes and Nour,2016).It has been suggested that aberrant salience attribution may arise from elevated dopaminergic neurotransmission.Mesostriatal dopamine signals play an important role in the processing of salience of stimuli (Bromberg-Martin et al.,2010),and increased responses of dopamine to neutral stimuli cause abnormal learning,which can be explained by increased dopamine activation.Increased aberrant salience is positively correlated with presynapticdopamine synthesis capacity in the striatum (Boehme et al.,2015).The capacities of presynaptic dopamine synthesis and release of dopamine in the striatum increase in patients with schizophrenia,the phasic dopamine responses of these patients may reflect inappropriate and chaotic phasic firing of dopamine neuron (Kapur,2003;Heinz and Schlagenhauf,2010).According to a meta-analysis of patients with Parkinson's disease who received levodopa,the addition of dopamine agonists resulted in the improvement of activities of daily living and motor score as well as the emergence of hallucinations (Talati et al.,2009).

THE RELATIONSHIP BETWEEN DOPAMINE LEVELS AND DOPAMINE FUNCTIONS FOLLOWS AN INVERTED U-SHAPED CURVE

DA levels and its function in the dopamine receptors exhibit an inverted U-shaped relationship,and excessively high or low dopamine levels impair dopamine function.Acute stress increases extracellular dopamine levels (Abercrombie et al.,1989),resulting in increased firing of dopaminergic neurons (Anstrom and Woodward,2005).In a research on attention deficit and hyperactivity disorder,the administration of lowdose dopamine agonist improved prefrontal cortical cognitive function,obtained from human as well as animal studies (Mehta et al.,2001;Kuczenski and Segal,2002;Arnsten and Dudley,2005).Conversely,excessive amounts of dopamine agonist reduce performance (Berridge et al.,2006;Dodds et al.,2008).In patients with Parkinson's disease,dopamine levels in the prefrontal cortex (PFC) changed their executive function,which deteriorated when the dopamine levels were high or low;thus,adequate dopamine levels will help achieve good executive function (Fallon et al.,2015;Murakami et al.,2017).

NEGATIVE CORRELATION BETWEEN ACTIVITY IN THE STRIATUM AND MIDBRAIN,AND PREFRONTAL CORTEX FUNCTION

Lateral PFC guides thoughts,attention,and behavior (Goldman-Rakic,1995),and it plays a primary role in executive function and motivation (Fuster,2001).The ventromedial PFC regulates emotion (Ongür and Price,2000).High levels of noradrenaline and dopamine receptor stimulation impair PFC function and strengthen functions the primary sensory corticies and striatum,orchestration of the brain's response patterns switches from reflective to reflexive brain state (Arnsten,2015).Higher aberrant salience attribution in patients with schizophrenia was negatively correlated with neural self-referential processing in ventromedial PFC (Pankow et al.,2016).It has been proposed that aberrant salience attribution is associated with impaired coding of prediction error and disordered dopamine release in the striatum;subcortical hyperdopaminergic state results in impaired PFC function.PFC dysfunction and psychotic symptoms developed from increased dopamine release lead to the deterioration of flexible and cautious thinking in the brain,which may result in impulsive and abnormal behavior.

A HALVED DOSE OF ANTIPSYCHOTICS RELIEVES POSITIVE SYMPTOMS AND IMPROVES PREFRONTAL CORTEX FUNCTION

A halved dose of antipsychotics in patients with schizophrenia who are receiving high-dose antipsychotic therapy weakens the blockade of dopamine and excessively increases dopamine levels;hence,it causes decreased dopamine transmission.Decreased dopamine transmission leads to reduced dopamine activation in the midbrain and striatum and may reduce positive symptoms.There is a negative correlation between the PFC and subcortical structures.Subcortical hyperdopaminergic state during the relapse phase results in PFC dysfunction.A reduced subcortical activity caused by a halved dose of antipsychotics may improve PFC function.The resolution of positive symptoms and improvement of PFC function may result in the control of impulsive and abnormal behavior and may contribute to remission.

CONCLUSIONS

Treatment with a halved dose of antipsychotics in patients with schizophrenia who relapse while receiving high-dose antipsychotic therapy may reduce or relieve positive symptoms and abnormal behavior.In the future,this treatment needs to be conducted in clinical trials.

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