Skip to main content
SpringerLink
Log in

Lack of association between dopaminergic antagonism and negative symptoms in schizophrenia: a positron emission tomography dopamine D2/3 receptor occupancy study

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Several pre-clinical studies suggest that antipsychotic medications cause secondary negative symptoms. However, direct evidence for a relationship among antipsychotic medications, their direct effects on neurotransmitter systems, and negative symptoms in schizophrenia remains controversial.

Objective

The objective of this study was to examine the relationship between antipsychotic-related dopamine D2/3 receptor occupancy and negative symptoms in patients with schizophrenia.

Methods

Forty-one clinically stable outpatients with schizophrenia participated in this prospective dose reduction positron emission tomography (PET) study. Clinical assessments and [11C]-raclopride PET scans were performed before and after participants underwent gradual dose reduction of their antipsychotic medication by up to 40 % from the baseline dose.

Results

No significant relationship was found between antipsychotic-related dopamine D2/3 receptor occupancy and negative symptom severity at baseline or follow-up. Similar null findings were found for subdomains of negative symptoms (amotivation and diminished expression). Occupancy was significantly lower following dose reduction; however, negative symptom severity did not change significantly, though a trend toward reduction was noted. Examination of change scores between these two variables revealed no systematic relationship.

Conclusions

Our cross-sectional and longitudinal results failed to find a significant dose-dependent relationship between severity of negative symptoms and antipsychotic-related dopaminergic antagonism in schizophrenia. These findings argue against the notion that antipsychotics necessarily cause secondary negative symptoms. Our results are also in contrast with the behavioral effects of dopaminergic antagonism routinely reported in pre-clinical investigations, suggesting that the role of this variable in the context of chronic treatment and schizophrenia needs to be re-examined.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Alexopoulos GS, Streim J, Carpenter D, Docherty JP (2004) Using antipsychotic agents in older patients. J Clin Psychiatry 65(Suppl 2):5–99 discussion 100-102; quiz 103-4

    PubMed  Google Scholar 

  • Amato D, Natesan S, Yavich L, Kapur S, Muller CP (2011) Dynamic regulation of dopamine and serotonin responses to salient stimuli during chronic haloperidol treatment. Int J Neuropsychopharmacol 14:1327–1339

    Article  CAS  PubMed  Google Scholar 

  • Appelbaum PS, Grisso T (2001) MacArthur competence assessment tool for clinical research (MacCAT-CR). Professional Resource Press, Sarasota, FL

    Google Scholar 

  • Artaloytia JF, Arango C, Lahti A, Sanz J, Pascual A, Cubero P, Prieto D, Palomo T (2006) Negative signs and symptoms secondary to antipsychotics: a double-blind, randomized trial of a single dose of placebo, haloperidol, and risperidone in healthy volunteers. Am J Psychiatry 163:488–493

    Article  PubMed  Google Scholar 

  • Barnes TR (1989) A rating scale for drug-induced akathisia. Br J Psychiatry 154:672–676

    Article  CAS  PubMed  Google Scholar 

  • Bleuler E (1950) Dementia praecox or the group of schizophrenias. International Universities Press, New York

    Google Scholar 

  • Breier A, Wolkowitz OM, Doran AR, Roy A, Boronow J, Hommer DW, Pickar D (1987) Neuroleptic responsivity of negative and positive symptoms in schizophrenia. Am J Psychiatry 144:1549–1555

    Article  CAS  PubMed  Google Scholar 

  • Carpenter WT Jr, Heinrichs DW, Wagman AM (1988) Deficit and nondeficit forms of schizophrenia: the concept. Am J Psychiatry 145:578–583

    Article  PubMed  Google Scholar 

  • Darbà J, Minoves A, Rojo E, Jimenez F, Rejas J (2011) Efficacy of second-generation-antipsychotics in the treatment of negative symptoms of schizophrenia: a meta-analysis of randomized clinical trials. Revista de Psiquiatría y Salud Mental (English Edition) 4:126–143

    Article  Google Scholar 

  • de Haan L, Lavalaye J, Linszen D, Dingemans PM, Booij J (2000) Subjective experience and striatal dopamine D(2) receptor occupancy in patients with schizophrenia stabilized by olanzapine or risperidone. Am J Psychiatry 157:1019–1020

    Article  PubMed  Google Scholar 

  • de Haan L, van Bruggen M, Lavalaye J, Booij J, Dingemans PM, Linszen D (2003) Subjective experience and D2 receptor occupancy in patients with recent-onset schizophrenia treated with low-dose olanzapine or haloperidol: a randomized, double-blind study. Am J Psychiatry 160:303–309

    Article  PubMed  Google Scholar 

  • Fervaha G, Foussias G, Agid O, Remington G (2014) Motivational and neurocognitive deficits are central to the prediction of longitudinal functional outcome in schizophrenia. Acta Psychiatr Scand 130:290–299

    Article  CAS  PubMed  Google Scholar 

  • Fervaha G, Foussias G, Takeuchi H, Agid O, Remington G (2015a) Measuring motivation in people with schizophrenia. Schizophr Res 169:423–426

    Article  PubMed  Google Scholar 

  • Fervaha G, Takeuchi H, Lee J, Foussias G, Fletcher PJ, Agid O, Remington G (2015b) Antipsychotics and amotivation. Neuropsychopharmacology 40:1539–1548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • First MB, Spitzer RL, Gibbon M, Williams JBW (2002) Structured Clinical Interview for DSM-IV-TR Axis I Disorders, research version, patient edition. (SCID-I/P). New York State Psychiatric Institute, New York, NY

    Google Scholar 

  • Fusar-Poli P, Papanastasiou E, Stahl D, Rocchetti M, Carpenter W, Shergill S, McGuire P (2015) Treatments of negative symptoms in schizophrenia: meta-analysis of 168 randomized placebo-controlled trials. Schizophr Bull 41:892–899

    Article  PubMed  Google Scholar 

  • Gardner DM, Murphy AL, O’Donnell H, Centorrino F, Baldessarini RJ (2010) International consensus study of antipsychotic dosing. Am J Psychiatry 167:686–693

    Article  PubMed  Google Scholar 

  • Graff-Guerrero A, Willeit M, Ginovart N, Mamo D, Mizrahi R, Rusjan P, Vitcu I, Seeman P, Wilson AA, Kapur S (2008) Brain region binding of the D2/3 agonist [11C]-(+)-PHNO and the D2/3 antagonist [11C]raclopride in healthy humans. Hum Brain Mapp 29:400–410

    Article  PubMed  Google Scholar 

  • Graff-Guerrero A, Rajji TK, Mulsant BH, Nakajima S, Caravaggio F, Suzuki T, Uchida H, Gerretsen P, Mar W, Pollock BG, Mamo DC (2015) Evaluation of antipsychotic dose reduction in late-life schizophrenia: a prospective dopamine D2/3 receptor occupancy study. JAMA Psychiatry 72:927–934

    Article  PubMed  Google Scholar 

  • Gunn RN, Lammertsma AA, Hume SP, Cunningham VJ (1997) Parametric imaging of ligand-receptor binding in PET using a simplified reference region model. NeuroImage 6:279–287

    Article  CAS  PubMed  Google Scholar 

  • Haber SN, Knutson B (2010) The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology 35:4–26

    Article  PubMed  Google Scholar 

  • Harris MJ, Heaton RK, Schalz A, Bailey A, Patterson TL (1997) Neuroleptic dose reduction in older psychotic patients. Schizophr Res 27:241–248

    Article  CAS  PubMed  Google Scholar 

  • Harvey PD, Davidson M, White L, Keefe RS, Hirschowitz J, Mohs RC, Davis KL (1996) Empirical evaluation of the factorial structure of clinical symptoms in schizophrenia: effects of typical neuroleptics on the brief psychiatric rating scale. Biol Psychiatry 40:755–760

    Article  CAS  PubMed  Google Scholar 

  • Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, Holden J, Houle S, Huang SC, Ichise M, Iida H, Ito H, Kimura Y, Koeppe RA, Knudsen GM, Knuuti J, Lammertsma AA, Laruelle M, Logan J, Maguire RP, Mintun MA, Morris ED, Parsey R, Price JC, Slifstein M, Sossi V, Suhara T, Votaw JR, Wong DF, Carson RE (2007) Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 27:1533–1539

    Article  CAS  PubMed  Google Scholar 

  • Juckel G, Schlagenhauf F, Koslowski M, Filonov D, Wustenberg T, Villringer A, Knutson B, Kienast T, Gallinat J, Wrase J, Heinz A (2006) Dysfunction of ventral striatal reward prediction in schizophrenic patients treated with typical, not atypical, neuroleptics. Psychopharmacology 187:222–228

    Article  CAS  PubMed  Google Scholar 

  • Kapur S, Mamo D (2003) Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuro-Psychopharmacol Biol Psychiatry 27:1081–1090

    Article  CAS  Google Scholar 

  • Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13:261–276

    Article  CAS  PubMed  Google Scholar 

  • Kegeles LS, Abi-Dargham A, Frankle WG, Gil R, Cooper TB, Slifstein M, Hwang DR, Huang Y, Haber SN, Laruelle M (2010) Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry 67:231–239

    Article  CAS  PubMed  Google Scholar 

  • Kelley ME, van Kammen DP, Allen DN (1999) Empirical validation of primary negative symptoms: independence from effects of medication and psychosis. Am J Psychiatry 156:406–411

    CAS  PubMed  Google Scholar 

  • Kirkpatrick B, Fenton WS, Carpenter WT Jr, Marder SR (2006) The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull 32:214–219

    Article  PubMed  PubMed Central  Google Scholar 

  • Knowles EE, David AS, Reichenberg A (2010) Processing speed deficits in schizophrenia: reexamining the evidence. Am J Psychiatry 167:828–835

    Article  PubMed  Google Scholar 

  • Kraepelin E (1919) Dementia praecox and paraphrenia. Livingstone, Edinburgh, UK

    Google Scholar 

  • Lahti AC, Weiler MA, Holcomb HH, Tamminga CA, Cropsey KL (2009) Modulation of limbic circuitry predicts treatment response to antipsychotic medication: a functional imaging study in schizophrenia. Neuropsychopharmacology 34:2675–2690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. NeuroImage 4:153–158

    Article  CAS  PubMed  Google Scholar 

  • Leucht S, Arbter D, Engel RR, Kissling W, Davis JM (2009) How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry 14:429–447

    Article  CAS  PubMed  Google Scholar 

  • Levinson DF, Simpson GM, Lo ES, Cooper TB, Singh H, Yadalam K, Stephanos MJ (1995) Fluphenazine plasma levels, dosage, efficacy, and side effects. Am J Psychiatry 152:765–771

    Article  CAS  PubMed  Google Scholar 

  • Luther L, Lysaker PH, Firmin RL, Breier A, Vohs JL (2015) Intrinsic motivation and amotivation in first episode and prolonged psychosis. Schizophr Res 169:418–422

    Article  PubMed  Google Scholar 

  • Marder SR, Aravagiri M, Wirshing WC, Wirshing DA, Lebell M, Mintz J (2002) Fluphenazine plasma level monitoring for patients receiving fluphenazine decanoate. Schizophr Res 53:25–30

    Article  CAS  PubMed  Google Scholar 

  • Mas S, Gasso P, Fernandez de Bobadilla R, Arnaiz JA, Bernardo M, Lafuente A (2013) Secondary nonmotor negative symptoms in healthy volunteers after single doses of haloperidol and risperidone: a double-blind, crossover, placebo-controlled trial. Hum Psychopharmacol 28:586–593

    Article  CAS  PubMed  Google Scholar 

  • Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang DR, Huang Y, Simpson N, Ngo K, Van Heertum R, Laruelle M (2001) Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab 21:1034–1057

    Article  CAS  PubMed  Google Scholar 

  • Messinger JW, Tremeau F, Antonius D, Mendelsohn E, Prudent V, Stanford AD, Malaspina D (2011) Avolition and expressive deficits capture negative symptom phenomenology: implications for DSM-5 and schizophrenia research. Clin Psychol Rev 31:161–168

    Article  PubMed  Google Scholar 

  • Miller DD, Flaum M, Arndt S, Fleming F, Andreasen NC (1994) Effect of antipsychotic withdrawal on negative symptoms in schizophrenia. Neuropsychopharmacology 11:11–20

    Article  CAS  PubMed  Google Scholar 

  • Nakajima S, Caravaggio F, Mamo DC, Mulsant BH, Chung JK, Plitman E, Iwata Y, Gerretsen P, Uchida H, Suzuki T, Mar W, Wilson AA, Houle S, Graff-Guerrero A (2015) Dopamine D2/3 receptor availability in the striatum of antipsychotic-free older patients with schizophrenia—a [11C]-raclopride PET study. Schizophr Res 164:263–267

    Article  PubMed  PubMed Central  Google Scholar 

  • Overall JE, Donald RG (1962) The brief psychiatric rating scale. Psychol Rep 10:799–812

    Article  Google Scholar 

  • Peralta V, Cuesta MJ, Martinez-Larrea A, Serrano JF (2000) Differentiating primary from secondary negative symptoms in schizophrenia: a study of neuroleptic-naive patients before and after treatment. Am J Psychiatry 157:1461–1466

    Article  CAS  PubMed  Google Scholar 

  • Prosser ES, Csernansky JG, Kaplan J, Thiemann S, Becker TJ, Hollister LE (1987) Depression, parkinsonian symptoms, and negative symptoms in schizophrenics treated with neuroleptics. J Nerv Ment Dis 175:100–105

    Article  CAS  PubMed  Google Scholar 

  • Saeedi H, Remington G, Christensen BK (2006) Impact of haloperidol, a dopamine D2 antagonist, on cognition and mood. Schizophr Res 85:222–231

    Article  PubMed  Google Scholar 

  • Sakurai H, Bies RR, Stroup ST, Keefe RS, Rajji TK, Suzuki T, Mamo DC, Pollock BG, Watanabe K, Mimura M, Uchida H (2013) Dopamine D2 receptor occupancy and cognition in schizophrenia: analysis of the CATIE data. Schizophr Bull 39:564–574

    Article  PubMed  Google Scholar 

  • Salamone JD, Correa M (2012) The mysterious motivational functions of mesolimbic dopamine. Neuron 76:470–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Samaha AN, Seeman P, Stewart J, Rajabi H, Kapur S (2007) “Breakthrough” dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neurosci 27:2979–2986

    Article  CAS  PubMed  Google Scholar 

  • Schlagenhauf F, Juckel G, Koslowski M, Kahnt T, Knutson B, Dembler T, Kienast T, Gallinat J, Wrase J, Heinz A (2008) Reward system activation in schizophrenic patients switched from typical neuroleptics to olanzapine. Psychopharmacology 196:673–684

    Article  CAS  PubMed  Google Scholar 

  • Schooler NR (1994) Deficit symptoms in schizophrenia: negative symptoms versus neuroleptic-induced deficits. Acta Psychiatr Scand Suppl 380:21–26

    Article  CAS  PubMed  Google Scholar 

  • Schultz SK, Miller DD, Oliver SE, Arndt S, Flaum M, Andreasen NC (1997) The life course of schizophrenia: age and symptom dimensions. Schizophr Res 23:15–23

    Article  CAS  PubMed  Google Scholar 

  • Simpson GM, Angus JW (1970) A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 212:11–19

    Article  CAS  Google Scholar 

  • Studholme C, Hill DL, Hawkes DJ (1997) Automated three-dimensional registration of magnetic resonance and positron emission tomography brain images by multiresolution optimization of voxel similarity measures. Med Phys 24:25–35

    Article  CAS  PubMed  Google Scholar 

  • Tugg LA, Desai D, Prendergast P, Remington G, Reed K, Zipursky RB (1997) Relationship between negative symptoms in chronic schizophrenia and neuroleptic dose, plasma levels and side effects. Schizophr Res 25:71–78

    Article  CAS  PubMed  Google Scholar 

  • van Erp TG, Preda A, Nguyen D, Faziola L, Turner J, Bustillo J, Belger A, Lim KO, McEwen S, Voyvodic J, Mathalon DH, Ford J, Potkin SG, Fbirn (2014) Converting positive and negative symptom scores between PANSS and SAPS/SANS. Schizophr Res 152:289–294

    Article  PubMed  Google Scholar 

  • Wallwork RS, Fortgang R, Hashimoto R, Weinberger DR, Dickinson D (2012) Searching for a consensus five-factor model of the positive and negative syndrome scale for schizophrenia. Schizophr Res 137:246–250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weickert TW, Goldberg TE, Marenco S, Bigelow LB, Egan MF, Weinberger DR (2003) Comparison of cognitive performances during a placebo period and an atypical antipsychotic treatment period in schizophrenia: critical examination of confounds. Neuropsychopharmacology 28:1491–1500

    Article  CAS  PubMed  Google Scholar 

  • Wilson AA, Garcia A, Jin L, Houle S (2000) Radiotracer synthesis from [(11)C]-iodomethane: a remarkably simple captive solvent method. Nucl Med Biol 27:529–532

    Article  CAS  PubMed  Google Scholar 

  • Zhang JP, Gallego JA, Robinson DG, Malhotra AK, Kane JM, Correll CU (2013) Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis. Int J Neuropsychopharmacol 16:1205–1218

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was funded by CIHR grant MOP-97946 (Dr. Graff-Guerrero), US National Institutes of Health grant RO1MH084886 (Dr. Graff-Guerrero), and a Vanier Canada Graduate Scholarship (Dr. Fervaha).

The positron emission tomography center staff at the Centre for Addiction and Mental Health, including Alvina Ng, BS, and Laura Nguyen, BS, provided technical assistance in data collection. The Multimodal Imaging Group Staff at the Centre for Addiction and Mental Health, including Thushanthi Balakumar, Zhe Feng, Kathryn Kalahani-Bargis, and Alex Naber, assisted in participants’ recruitment and data administration.

Author information

Authors and Affiliations

  1. Schizophrenia Division, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Gagan Fervaha, Gary Remington & Ariel Graff-Guerrero

  2. Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada

    Gagan Fervaha, Fernando Caravaggio, Benoit H. Mulsant, Bruce G. Pollock, Shinichiro Nakajima, Philip Gerretsen, Tarek K. Rajji, Yusuke Iwata, Eric Plitman, Jun Ku Chung, Gary Remington & Ariel Graff-Guerrero

  3. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    Gagan Fervaha, Fernando Caravaggio, Gary Remington & Ariel Graff-Guerrero

  4. Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada

    David C. Mamo, Shinichiro Nakajima, Philip Gerretsen, Wanna Mar, Yusuke Iwata, Eric Plitman, Jun Ku Chung & Ariel Graff-Guerrero

  5. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Benoit H. Mulsant, Bruce G. Pollock, Shinichiro Nakajima, Philip Gerretsen, Tarek K. Rajji, Yusuke Iwata, Gary Remington & Ariel Graff-Guerrero

  6. Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Benoit H. Mulsant, Bruce G. Pollock, Shinichiro Nakajima, Philip Gerretsen, Tarek K. Rajji, Yusuke Iwata, Eric Plitman, Jun Ku Chung & Ariel Graff-Guerrero

Authors
  1. Gagan Fervaha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fernando Caravaggio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David C. Mamo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Benoit H. Mulsant
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bruce G. Pollock
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shinichiro Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Philip Gerretsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tarek K. Rajji
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wanna Mar
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yusuke Iwata
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Eric Plitman
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jun Ku Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Gary Remington
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Ariel Graff-Guerrero
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ariel Graff-Guerrero.

Ethics declarations

The study was approved by the institutional Research Ethics Board, authorized by Health Canada, and registered at ClinicalTrials.gov (NCT00716755). All participants had to be deemed competent to provide consent as per the MacArthur Competence Assessment Tool for Clinical Research (Appelbaum and Grisso 2001) and provided written informed consent before the initiation of any study procedures.

Conflict of interest

Dr. Mamo has received research support from Pfizer.

Dr. Mulsant has received research support from Brain Canada, Centre for Addiction and Mental Health (CAMH) Foundation, CIHR, US NIH. He has also received medications for NIH-funded clinical trials from Bristol-Myers Squibb, Eli-Lilly and Company, and Pfizer. He directly own stocks of General Electric (<$5000).

Dr. Nakajima has received fellowship grants from the CIHR, Japan Society for the Promotion of Science, and Nakatomi Foundation and manuscript fees from Dainippon-Sumitomo Pharma and Kyowa Hakko Kirin.

Dr. Gerretsen has received fellowship support from the CAMH Foundation, OMHF, and CIHR.

Dr. Rajji received research support from Brain Canada, Brain and Behavior Research Foundation, Canada Research Chair, Canadian Foundation for Innovation, CIHR, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, the US NIH, and the W. Garfield Weston Foundation.

Dr. Remington has received research support from the Schizophrenia Society of Ontario, CIHR, Research Hospital Fund—Canada Foundation for Innovation, Canadian Diabetes Association, Novartis Canada, Medicure Inc., and Neurocrine Bioscience; as a co-investigator, he has received research support from the Canadian Psychiatric Research Foundation and Pfizer Inc.; consultant fees from Laboratorios Farmacéuticos ROVI, Synchroneuron, Novartis, and Roche; and speaker’s fees from Novartis.

Dr. Graff-Guerrero has received support from Brain Canada, Canadian Foundation for Innovation, CIHR, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, the US National Institute of Health (NIH), Ontario Mental Health Foundation (OMHF), Consejo Nacional de Ciencia y Tecnologia (CONACyT), Instituto de Ciencia y Tecnología del DF (ICyTDF), and Brain and Behavior Research Foundation.

The other authors declare that they have no conflict of interest.

Electronic supplementary material

ESM 1

(DOCX 25 kb)

ESM 2

(DOCX 25 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fervaha, G., Caravaggio, F., Mamo, D.C. et al. Lack of association between dopaminergic antagonism and negative symptoms in schizophrenia: a positron emission tomography dopamine D2/3 receptor occupancy study. Psychopharmacology 233, 3803–3813 (2016). https://doi.org/10.1007/s00213-016-4415-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-016-4415-6

Keywords

Search

Navigation