• Users Online: 422
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
Previous article Browse articles Next article 
REVIEW
Asia Pac J Clin Trials Nerv Syst Dis 2019,  4:72

Treatment with a halved dose of antipsychotics in patients with schizophrenia who relapse while receiving high-dose antipsychotic therapy


Juntendo Psychiatric Research Institute, Juntendo University, Tokyo, Japan

Date of Submission16-Apr-2019
Date of Acceptance22-Jun-2019
Date of Web Publication7-Aug-2019

Correspondence Address:
Ryota Ataniya
Juntendo Psychiatric Research Institute, Juntendo University, Tokyo
Japan
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2542-3932.263671

Rights and Permissions
  Abstract 


This study proposed and discussed a new treatment for patients with schizophrenia who relapse while receiving high-dose antipsychotic therapy. There is no drug therapy available for such patients. However, antipsychotic dose reduction by half may lead to remission. The positive symptoms of schizophrenia relate to increased striatal presynaptic dopamine availability and chaotic phasic firing of dopaminergic neurons in the striatum. Dopamine levels and its function in dopamine receptors show an inverted U-shaped curve relationship, which indicates that excessively high or low dopamine levels result in decreased dopamine activation. A halved dose of antipsychotics leads to excessive increase in subcortical dopamine levels and decreased dopamine function, resulting in the improvement of positive symptoms. Furthermore, there is a negative correlation between subcortical dopamine activity and the prefrontal cortex function; therefore, reduced mesostriatal dopamine activity may lead to increased prefrontal cortex function. The recovery of prefrontal cortex function may minimize impulsive or risk behaviors. The incidence of adverse events is similar after abrupt withdrawal or tapering of antipsychotics, except for the emergence of withdrawal dyskinesia. A halved dose of antipsychotics is effective for patients with schizophrenia who relapse while receiving high-dose antipsychotic therapy. Thus, we investigated whether an abrupt change to halved dose of antipsychotics improves positive symptoms and evaluated the efficacy of such treatment.

Keywords: schizophrenia; antipsychotics, high dose; relapse; dopamine; pharmacotherapy


How to cite this article:
Ataniya R. Treatment with a halved dose of antipsychotics in patients with schizophrenia who relapse while receiving high-dose antipsychotic therapy. Asia Pac J Clin Trials Nerv Syst Dis 2019;4:72-5

How to cite this URL:
Ataniya R. Treatment with a halved dose of antipsychotics in patients with schizophrenia who relapse while receiving high-dose antipsychotic therapy. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2019 [cited 2019 Oct 15];4:72-5. Available from: http://www.actnjournal.com/text.asp?2019/4/3/72/263671




  Drug Therapy and Relapse in Patients with Schizophrenia Top


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 Top


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 Top


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 Top


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 Top


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 Top


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 reward-related 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 Top


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 low-dose 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 Top


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 Top


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 Top


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.

Author contributions

The author confirms being the sole contributor of this work.

Conflicts of interest

The authors declare no conflicts of interest.

Financial support

None.

Copyright license agreement

The Copyright License Agreement has been signed by all authors before publication.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

C-Editors: Zhao M, Yu J; T-Editor: Jia Y



 
  References Top

1.
Abercrombie ED, Keefe KA, DiFrischia DS, Zigmond MJ (1989) Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex. J Neurochem 52:1655-1658.  Back to cited text no. 1
    
2.
Anstrom KK, Woodward DJ (2005) Restraint increases dopaminergic burst firing in awake rats. Neuropsychopharmacology 30:1832-1840.  Back to cited text no. 2
    
3.
Arnsten AF (2015) Stress weakens prefrontal networks: molecular insults to higher cognition. Nat Neurosci 18:1376-1385.  Back to cited text no. 3
    
4.
Arnsten AF, Dudley AG (2005) Methylphenidate improves prefrontal cortical cognitive function through alpha2 adrenoceptor and dopamine D1 receptor actions: relevance to therapeutic effects in attention deficit hyperactivity disorder. Behav Brain Funct 1:2.  Back to cited text no. 4
    
5.
Ascher-Svanum H, Zhu B, Faries DE, Salkever D, Slade EP, Peng X, Conley RR (2010) The cost of relapse and the predictors of relapse in the treatment of schizophrenia. BMC Psychiatry 10:2.  Back to cited text no. 5
    
6.
Berridge CW, Devilbiss DM, Andrzejewski ME, Arnsten AF, Kelley AE, Schmeichel B, Hamilton C, Spencer RC (2006) Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry 60:1111-1120.  Back to cited text no. 6
    
7.
Boehme R, Deserno L, Gleich T, Katthagen T, Pankow A, Behr J, Buchert R, Roiser JP, Heinz A, Schlagenhauf F (2015) Aberrant salience is related to reduced reinforcement learning signals and elevated dopamine synthesis capacity in healthy adults. J Neurosci 35:10103-10111.  Back to cited text no. 7
    
8.
Bromberg-Martin ES, Matsumoto M, Hikosaka O (2010) Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68:815-834.  Back to cited text no. 8
    
9.
Diaconescu AO, Jensen J, Wang H, Willeit M, Menon M, Kapur S, McIntosh AR (2011) Aberrant effective connectivity in schizophrenia patients during appetitive conditioning. Front Hum Neurosci 4:239.  Back to cited text no. 9
    
10.
Dodds CM, Muller U, Clark L, van Loon A, Cools R, Robbins TW (2008) Methylphenidate has differential effects on blood oxygenation level-dependent signal related to cognitive subprocesses of reversal learning. J Neurosci 28:5976-5982.  Back to cited text no. 10
    
11.
Emsley R, Nuamah I, Gopal S, Hough D, Fleischhacker WW (2018) Relapse after antipsychotic discontinuation in schizophrenia as a withdrawal phenomenon vs illness recurrence: a post hoc analysis of a randomized placebo-controlled study. J Clin Psychiatry 79:17m11874.  Back to cited text no. 11
    
12.
Esslinger C, Englisch S, Inta D, Rausch F, Schirmbeck F, Mier D, Kirsch P, Meyer-Lindenberg A, Zink M (2012) Ventral striatal activation during attribution of stimulus saliency and reward anticipation is correlated in unmedicated first episode schizophrenia patients. Schizophr Res 140:114-121.  Back to cited text no. 12
    
13.
Fallon SJ, Smulders K, Esselink RA, van de Warrenburg BP, Bloem BR, Cools R (2015) Differential optimal dopamine levels for set-shifting and working memory in Parkinson’s disease. Neuropsychologia 77:42-51.  Back to cited text no. 13
    
14.
Fusar-Poli P, Meyer-Lindenberg A (2013) Striatal presynaptic dopamine in schizophrenia, part II: meta-analysis of [(18)F/(11)C]-DOPA PET studies. Schizophr Bull 39:33-42.  Back to cited text no. 14
    
15.
Fuster JM (2001) The prefrontal cortex--an update: time is of the essence. Neuron 30:319-333.  Back to cited text no. 15
    
16.
Gilbert PL, Harris MJ, McAdams LA, Jeste DV (1995) Neuroleptic withdrawal in schizophrenic patients. A review of the literature. Arch Gen Psychiatry 52:173-188.  Back to cited text no. 16
    
17.
Goldman-Rakic PS (1995) Cellular basis of working memory. Neuron 14:477-485.  Back to cited text no. 17
    
18.
Heinz A, Schlagenhauf F (2010) Dopaminergic dysfunction in schizophrenia: salience attribution revisited. Schizophr Bull 36:472-485.  Back to cited text no. 18
    
19.
Horga G, Cassidy CM, Xu X, Moore H, Slifstein M, Van Snellenberg JX, Abi-Dargham A (2016) Dopamine-related disruption of functional topography of striatal connections in unmedicated patients with schizophrenia. JAMA Psychiatry 73:862-870.  Back to cited text no. 19
    
20.
Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III--the final common pathway. Schizophr Bull 35:549-562.  Back to cited text no. 20
    
21.
Howes OD, Nour MM (2016) Dopamine and the aberrant salience hypothesis of schizophrenia. World Psychiatry 15:3-4.  Back to cited text no. 21
    
22.
Howes OD, McCutcheon R, Owen MJ, Murray RM (2017) The role of genes, stress, and dopamine in the development of schizophrenia. Biol Psychiatry 81:9-20.  Back to cited text no. 22
    
23.
Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S (2012) The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry 69:776-786.  Back to cited text no. 23
    
24.
Jensen J, Willeit M, Zipursky RB, Savina I, Smith AJ, Menon M, Crawley AP, Kapur S (2008) The formation of abnormal associations in schizophrenia: neural and behavioral evidence. Neuropsychopharmacology 33:473-479.  Back to cited text no. 24
    
25.
Juckel G (2016) Inhibition of the reward system by antipsychotic treatment. Dialogues Clin Neurosci 18:109-114.  Back to cited text no. 25
    
26.
Kambeitz J, Abi-Dargham A, Kapur S, Howes OD (2014) Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies. Br J Psychiatry 204:420-429.  Back to cited text no. 26
    
27.
Kane JM, Leucht S, Carpenter D, Docherty JP; Expert Consensus Panel for Optimizing Pharmacologic Treatment of Psychotic Disorders (2003) The expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. Introduction: methods, commentary, and summary. J Clin Psychiatry 64 Suppl 12:5-19.  Back to cited text no. 27
    
28.
Kapur S (2003) Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 160:13-23.  Back to cited text no. 28
    
29.
Kapur S, Remington G (2001) Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry 50:873-883.  Back to cited text no. 29
    
30.
Kuczenski R, Segal DS (2002) Exposure of adolescent rats to oral methylphenidate: preferential effects on extracellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine. J Neurosci 22:7264-7271.  Back to cited text no. 30
    
31.
Lafeuille MH, Gravel J, Lefebvre P, Fastenau J, Muser E, Doshi D, Duh MS (2013) Patterns of relapse and associated cost burden in schizophrenia patients receiving atypical antipsychotics. J Med Econ 16:1290-1299.  Back to cited text no. 31
    
32.
Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R (1999) Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 46:56-72.  Back to cited text no. 32
    
33.
Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D’Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB (1996) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A 93:9235-9240.  Back to cited text no. 33
    
34.
Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, Kreyenbuhl J, American Psychiatric Association, Steering Committee on Practice Guidelines (2004) Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 161:1-56.  Back to cited text no. 34
    
35.
Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G, Davis JM (2012) Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 379:2063-2071.  Back to cited text no. 35
    
36.
Mehta MA, Sahakian BJ, Robbins TW (2001) Comparative psychopharmacology of methylphenidate and related drugs in human volunteers, patients with ADHD, and experimental animals. In: Stimulant Drugs and ADHD: Basic and Clinical Neuroscience (Solanto MV, Arnsten AFT, Castellanos FX, eds), pp 303-331. New York, USA: Oxford University Press.  Back to cited text no. 36
    
37.
Murakami H, Nohara T, Shozawa H, Owan Y, Kuroda T, Yano S, Kezuka M, Kawamura M, Ono K (2017) Effects of dopaminergic drug adjustment on executive function in different clinical stages of Parkinson’s disease. Neuropsychiatr Dis Treat 13:2719-2726.  Back to cited text no. 37
    
38.
Murray GK, Corlett PR, Clark L, Pessiglione M, Blackwell AD, Honey G, Jones PB, Bullmore ET, Robbins TW, Fletcher PC (2008) Substantia nigra/ventral tegmental reward prediction error disruption in psychosis. Mol Psychiatry 13:239, 267-276.  Back to cited text no. 38
    
39.
Nielsen MØ, Rostrup E, Wulff S, Bak N, Lublin H, Kapur S, Glenthøj B (2012) Alterations of the brain reward system in antipsychotic naïve schizophrenia patients. Biol Psychiatry 71:898-905.  Back to cited text no. 39
    
40.
Olivares JM, Sermon J, Hemels M, Schreiner A (2013) Definitions and drivers of relapse in patients with schizophrenia: a systematic literature review. Ann Gen Psychiatry 12:32.  Back to cited text no. 40
    
41.
Ongür D, Price JL (2000) The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex 10:206-219.  Back to cited text no. 41
    
42.
Pankow A, Katthagen T, Diner S, Deserno L, Boehme R, Kathmann N, Gleich T, Gaebler M, Walter H, Heinz A, Schlagenhauf F (2016) Aberrant salience is related to dysfunctional self-referential processing in psychosis. Schizophr Bull 42:67-76.  Back to cited text no. 42
    
43.
Pessiglione M, Seymour B, Flandin G, Dolan RJ, Frith CD (2006) Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans. Nature 442:1042-1045.  Back to cited text no. 43
    
44.
Romaniuk L, Honey GD, King JR, Whalley HC, McIntosh AM, Levita L, Hughes M, Johnstone EC, Day M, Lawrie SM, Hall J (2010) Midbrain activation during Pavlovian conditioning and delusional symptoms in schizophrenia. Arch Gen Psychiatry 67:1246-1254.  Back to cited text no. 44
    
45.
Rutledge RB, Lazzaro SC, Lau B, Myers CE, Gluck MA, Glimcher PW (2009) Dopaminergic drugs modulate learning rates and perseveration in Parkinson’s patients in a dynamic foraging task. J Neurosci 29:15104-15114.  Back to cited text no. 45
    
46.
Schott BH, Minuzzi L, Krebs RM, Elmenhorst D, Lang M, Winz OH, Seidenbecher CI, Coenen HH, Heinze HJ, Zilles K, Düzel E, Bauer A (2008) Mesolimbic functional magnetic resonance imaging activations during reward anticipation correlate with reward-related ventral striatal dopamine release. J Neurosci 28:14311-14319.  Back to cited text no. 46
    
47.
Schultz W (2013) Updating dopamine reward signals. Curr Opin Neurobiol 23:229-238.  Back to cited text no. 47
    
48.
Talati R, Baker WL, Patel AA, Reinhart K, Coleman CI (2009) Adding a dopamine agonist to preexisting levodopa therapy vs. levodopa therapy alone in advanced Parkinson’s disease: a meta analysis. Int J Clin Pract 63:613-623.  Back to cited text no. 48
    
49.
Weinberger DR, Laruelle M (2002) Neurochemical and neuropharmacological imaging in schizophrenia. In: Neuropsychopharmacology: The Fifth Generation of Progress (Davis KL, Charney D, Coyle JT, Nemeroff C, eds), pp 833-855. Philadelphia, PA, USA: Lippincott, Williams, & Wilkins.  Back to cited text no. 49
    
50.
Weinstein JJ, Chohan MO, Slifstein M, Kegeles LS, Moore H, Abi-Dargham A (2017) Pathway-specific dopamine abnormalities in schizophrenia. Biol Psychiatry 81:31-42.  Back to cited text no. 50
    




 

Top
Previous article  Next article
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  Drug Therapy and...Definition of Re...A Halved Dose of...Causes of Relaps...Dopamine Functio...The Relationship...Negative Correla...A Halved Dose of...
  In this article
Abstract
Search Strategy
Conclusions
References

 Article Access Statistics
    Viewed374    
    Printed44    
    Emailed0    
    PDF Downloaded34    
    Comments [Add]    

Recommend this journal