The relationship between striatal dopamine and anterior cingulate glutamate in first episode psychosis changes with antipsychotic treatment

ABSTRACT The neuromodulator dopamine and excitatory neurotransmitter glutamate have both been implicated in the pathogenesis of psychosis, and dopamine antagonists remain the predominant

treatment for psychotic disorders. To date no study has measured the effect of antipsychotics on both of these indices together, in the same population of people with psychosis. Striatal

dopamine synthesis capacity (Kicer) and anterior cingulate glutamate were measured using 18F-DOPA positron emission tomography and proton magnetic resonance spectroscopy respectively, before

and after at least 5 weeks’ naturalistic antipsychotic treatment in people with first episode psychosis (_n_ = 18) and matched healthy controls (_n_ = 20). The relationship between both

measures at baseline and follow-up, and the change in this relationship was analyzed using a mixed linear model. Neither anterior cingulate glutamate concentrations (_p_ = 0.75) nor striatal

Kicer (_p_ = 0.79) showed significant change following antipsychotic treatment. The change in relationship between whole striatal Kicer and anterior cingulate glutamate, however, was

statistically significant (_p_ = 0.017). This was reflected in a significant difference in relationship between both measures for patients and controls at baseline (_t_ = 2.1, _p_ = 0.04),

that was not present at follow-up (t = 0.06, p = 0.96). Although we did not find any effect of antipsychotic treatment on absolute measures of dopamine synthesis capacity and anterior

cingulate glutamate, the relationship between anterior cingluate glutamate and striatal dopamine synthesis capacity did change, suggesting that antipsychotic treatment affects the

relationship between glutamate and dopamine. SIMILAR CONTENT BEING VIEWED BY OTHERS GLUTAMATERGIC BASIS OF ANTIPSYCHOTIC RESPONSE IN FIRST-EPISODE PSYCHOSIS: A DUAL VOXEL STUDY OF THE

ANTERIOR CINGULATE CORTEX Article 26 September 2023 CLINICAL CORRELATION BUT NO ELEVATION OF STRIATAL DOPAMINE SYNTHESIS CAPACITY IN TWO INDEPENDENT COHORTS OF MEDICATION-FREE INDIVIDUALS

WITH SCHIZOPHRENIA Article 17 November 2021 THE RELATIONSHIP BETWEEN CORTICAL SYNAPTIC TERMINAL DENSITY MARKER SV2A AND GLUTAMATE EARLY IN THE COURSE OF SCHIZOPHRENIA: A MULTIMODAL PET AND

MRS IMAGING STUDY Article Open access 01 March 2025 INTRODUCTION The dopamine hypothesis of psychosis remains one of the predominant biological theories within psychiatry [1,2,3,4], and one

central strand is the clinical efficacy of dopamine D2 antagonists [5,6,7,8]. Dopamine interactions with other neurotransmitter systems have been implicated in psychosis, these including

GABA [9], serotonin [10] and the endocannabinoid system [11], though the majority of literature has examined the excitatory neurotransmitter, glutamate [12]. Pre-clinical models show

interactions between the dopamine and glutamate systems which could contribute to the actions of antipsychotics [12]. Microdialysis experiments show dopamine antagonists cause an acute

increase in extracellular dopamine, which reverts to baseline levels upon chronic treatment [13]. Rodent spectroscopy suggests effects of antipsychotics on frontal cortex glutamate, with

olanzapine and clozapine decreasing this, though no change was seen with aripiprazole, haloperidol or risperidone [14]. Moreover, drug challenge studies have demonstrated targeting one

system may have reciprocal effects, for example, acute ketamine increasing cortical, striatal and nucleus accumbens dopamine in-vivo [15]. Striatal dopamine synthesis capacity (Kicer) can be

measured in-vivo using positron emission tomography, and cortical glutamate can be measured using proton magnetic resonance spectroscopy (MRS). Effects on separate components of the

dopamine and glutamate systems have been examined in few in-vivo studies [16] but not together in the same population. One study showed a decrease in Kicer with sub-chronic haloperidol in 9

people with schizophrenia free of antipsychotic medication [17], whilst another found no difference in whole striatal Kicer in 17 people with first episode psychosis, initially not taking

antipsychotic medication, who were then treated naturalistically with second generation antipsychotics [18]. A systematic review of in-vivo MRS studies found a small decrease in Glx

(glutamate + glutamine) in some brain regions following antipsychotic treatment [19], another study showing reduction in anterior cingulate cortex (ACC) glutamate in people with first

episode schizophrenia [20]. Conversely, a recent study in 61 people with schizophrenia failed to show any change in ACC or hippocampal glutamate after 6 weeks' risperidone treatment

[21]. In-vivo examination of both systems in the same population has been limited to two cross-sectional studies. A study in healthy volunteers reported a direct relationship between medial

prefrontal cortex glutamate and striatal dopamine synthesis capacity [22]. While in people with first episode psychosis, we reported an inverse correlation between ACC glutamate and striatal

Kicer [23]. We are unaware of studies examining effects of antipsychotics on both systems in the same people, which is necessary if one wishes to examine interactions between both systems.

In the current study we obtained measures of both anterior cingulate glutamate concentrations, and striatal dopamine synthesis capacity, before and after treatment with antipsychotics, in

the same cohort of individuals with first episode psychosis. We hypothesized no overall within-subject change in Kicer or glutamate, instead predicting that antipsychotics would produce more

subtle circuit-level changes in both neurotransmitters, reflected in a change in the relationship between the two measure pre- and post-treatment. METHODS AND MATERIALS Ethical approval was

given by East of England-Cambridge East Ethics Committee, and the Administration of Radioactive Substances Advisory Committee (ARSAC). All participants provided informed written consent.

The patient group had scans at baseline and after antipsychotic treatment, the healthy control sample having scans solely at baseline. PARTICIPANTS Patients (_N_ = 18) were recruited from

London first episode psychosis (FEP) services and were required to be experiencing their first episode of psychotic illness, antipsychotic naïve, free of antipsychotics for >6 weeks or

minimally treated with antipsychotics for <2 weeks. For inclusion, subjects required a diagnosis of a psychotic disorder meeting International Classification of Disease-10 (ICD 10)

criteria [24], and experience psychotic symptoms, defined as at least moderate severity on one or more of the delusion (P1), hallucination (P3), and persecution (P6) items on the Positive

and Negative Syndrome Scale (PANSS), consistent with previous studies [24, 25]. Diagnosis was confirmed by a study psychiatrist (SJ), using a structured instrument (Mini-international

Neuropsychiatric Interview (MINI)) [26]. Inclusion criteria required people with psychosis to be antipsychotic naïve, antipsychotic-free for at least 6 weeks, or “minimally treated”

(receiving antipsychotic medication for 2 weeks or less). Healthy control subjects (_N_ = 20) were recruited from the same geographical area as the patient group. Inclusion criteria for

controls were: no personal history of psychiatric illness (assessed using the MINI) and no concurrent psychotropic medication (through self-report). Exclusion criteria for all participants

were: history of significant head trauma (any loss of consciousness due to head injury), dependence on illicit substances (defined using the MINI), medical co-morbidity (other than minor

illnesses), family history of psychosis and contra-indications to scanning (such as pregnancy). Nicotine and alcohol use were permitted, though specific restrictions were placed on the day

of PET. ANTIPSYCHOTIC TREATMENT All antipsychotic doses were required to be within therapeutic range, defined in the Maudsley Prescribing Guidelines [27]. Use of other psychotropic

medication (such as antidepressants and benzodiazepines) was permitted. To assess concordance we used a multisource approach, requiring evidence of adequate adherence on at least two of the

following: antipsychotic plasma levels, pharmacy and electronic medical records, and self-report from the patient and an independent source (family member/caregiver or health care

professional). Adequate concordance was defined as taking a minimum of 80% of prescribed doses, in line with consensus recommendations [28]. To measure antipsychotic exposure, we determined

chlorpromazine-equivalent dose years, as described by Andreasen et al. [29]. In the cases of lurasidone and amisulpride, we used the method described by Leucht et al. [30], using data from

the Maudsley Prescribing Guidelines [27], because these are not covered in Andreasen et al. CLINICAL MEASURES Symptoms were measured using the positive and negative syndrome scale (PANSS),

with raters blinded to imaging results. Age, gender and ethnicity (white/non-white) were also recorded. PET IMAGING ACQUISITION AND ANALYSIS All participants were asked not to eat or drink

(except water), and refrain from alcohol for 12 h prior to scan. Imaging data were obtained on a Siemens Biograph 6 HiRez PET scanner (Siemens, Erlangen, Germany) in three-dimensional mode.

One hour before scan, participants received 400 mg entacapone, a peripheral catechol-_o_-methyl-transferase inhibitor to prevent formation of radiolabeled metabolites that may cross the

blood–brain barrier, and 150 mg carbidopa, a peripheral aromatic acid decarboxylase inhibitor to increase the PET imaging signal. Participants were positioned in the scanner with the

orbitomeatal line parallel to the transaxial plane of the tomograph. Head position was marked, monitored and movement minimized using a head strap. After acquiring a CT scan for attenuation

correction, ~150 MBq 18F-DOPA was administered by bolus intravenous injection, 30 s after the start of PET imaging. PET data were acquired in 32 frames of increasing duration over the 95-min

scan (frame intervals: 8 × 15 s, 3 × 60 s, 5 × 120 s, 16 × 300 s). Correction for head movement during scan was performed by employing a mutual information algorithm, described in prior

publications [30, 31]. SPM 8 [31, 32] was used to automatically normalize a tracer-specific 18F-DOPA template [32, 33] together with the striatal brain atlas as defined by Martinez et al.

[33, 34]. The primary outcome measure, the striatal influx constant for whole striatum with cerebellum as the reference region, Kicer (1/min), was calculated using the Patlak-Gjedde

graphical approach adapted for a reference tissue input function, used in prior studies by our group [24, 25, 30, 31, 34, 35]. MRS ACQUISITION All scans were acquired on a General Electric

(Milwaukee, Wisconsin, USA) Signa HDxt 3 Tesla MRI scanner. Internal localizer scans were used to determine the anterior commissure-posterior commissure line and inter-hemispheric angle. For

the voxel placements, 3D coronal inversion recovery prepared spoiled gradient echo (IR-SPGR) scans were acquired, followed by auto pre-scans for optimization of water suppression and

shimming. A T1 weighted structural scan was also obtained and was used for subsequent segmentation and CSF correction. 1H-MRS spectra were acquired for the anterior cingulate

region-of-interest (right-left 20 mm × anterior-posterior 20 mm x superior-inferior 20 mm). The anterior cingulate cortex voxel was prescribed from the midline sagittal localizer, with the

centre of the 20 × 20 × 20 mm voxel placed 13 mm above the genu of corpus callosum perpendicular to the AC–PC line to minimize inclusion of white matter and cerebral spinal fluid (CSF).

1H-MRS spectra (Point RESolves Spectroscopy (PRESS), TE = 30 ms, TR = 2 s) were obtained through the PROton Brain Examination (PROBE) sequence by GE, which includes water suppression. MRS

ANALYSIS Water-scaled metabolites, using a standard basis set of 16 metabolites (L-alanine, aspartate, creatine, phosphocreatine, GABA, glucose, Gln, glutamate, glycerophosphocholine,

glycine, myo-inositol, L-lactate, N-acetylaspartate, N-acetylaspartylglutamate, phosphocholine, and taurine), provided with LCModel and generated using same field strength (3 Tesla),

localization sequence (PRESS), and echo time (30 msec)/ The acquired data were analyzed using LC-model 6.3-I0 [36] and we specifically estimated levels of glutamate, in keeping with our

previous study, which highlighted the relationship between whole striatal 18F-DOPA PET and anterior cingulate Glutamate, in people with first episode psychosis [23]. Spectra were visually

inspected and metabolite analyses were restricted to spectra with line width (full-width at half-maximum; FWHM) ≤ 0.1 ppm, Cramér-Rao lower bounds (CRLB) for glutamate ≤ 20%, signal to noise

ratio ≥ 5. Corrections were applied to account for relative distribution of cerebrospinal fluid within anterior cingulate. In-house scripts were used to identify relative distribution of

white, grey matter and cerebrospinal fluid in the voxel prescribed to the anterior cingulate. The following correction was subsequently applied in order to correct for CSF content within the

voxel; where M raw metabolite value, WM white matter and GM grey matter: $${{{\mathrm{Mcorr}}}} = {{{\mathrm{M}}}} \ast ({{{\mathrm{WM}}}} + {{{\mathrm{GM}}}} \ast 1.22 + {{{\mathrm{CSF}}}}

\ast 1.55)/({{{\mathrm{WM}}}} + {{{\mathrm{GM}}}})$$ STATISTICAL ANALYSIS Analyses were performed using Stata version 13 [37] and R version 3.3.2 [38]. Linear mixed effect models were

constructed to determine effects of treatment on dopamine synthesis capacity, glutamate concentration, and the relationship between them. Our primary analysis investigated whether the

association between striatal Kicer and anterior cingulate glutamate observed in the patient group at baseline changed following antipsychotic treatment. In this analysis Kicer was the

dependent variable. Glutamate, timepoint (baseline vs follow-up), and a glutamate * time point interaction were included as fixed effects, with a random participant-level effect. The effect

of treatment on glutamate and dopamine individually was examined with a linear mixed model in which the neurochemical measure in question was the dependent variable, time point was a fixed

effect, with a random participant-level effect. Secondary analyses investigated whether striatal Kicer or anterior cingulate glutamate changed individually. In these analyses the

neurochemical measure was the dependent variable, while time was included as a fixed effect, with a random participant-level effect. In addition dopamine-glutamate association in patients

was compared with the association observed in controls, by fitting a linear model with Kicer as the dependent variable, and glutamate, group and glutamate* group interaction as independent

variables. This model was fitted separately for baseline and follow-up scans for the patient group RESULTS STUDY PARTICIPANTS 20 healthy controls received baseline scans, while 18 people

with first episode psychosis (FEP) received both baseline and follow-up scans and clinical assessment. Demographic details are given in Table 1. There were no significant differences between

patients and controls in age, gender or ethnicity. There was no statistical difference between groups, in terms of illicit drug use (self-report) or urine drug screen, nicotine or alcohl

use (self-report). At baseline the mean total PANSS in the patient group was 73.8 (SD 16.0) which reduced at a statistically significant level (_p_ < 0.01) to 52.9 (SD 19.6) following

antipsychotic treatment. Time between PET and MRS was as follows. Baseline; median 3.5 days (IQR = 5.75) Follow-up; median 5.5 days (IQR 17.5 days). At baseline, ten patients were

antipsychotic naïve, five were medication free and three were minimally treated. All patients received a minimum of 4 weeks’ antipsychotic treatment between baseline and follow-up scans.

PSYCHOTROPIC MEDICATION One patient was using Sertraline at baseline, and one taking benzodiazepines at follow-up. Psychotropic medication during the study is given in Table 2. The median

chlorpromazine dose years of antipsychotic treatment was 0.32 (IQR 0.17). CHANGE IN DOPAMINE AND GLUTAMATE MEASURES As reported in a sub-sample of these patients [18], there was no

significant change in whole striatal Kicer with antipsychotic treatment (coefficient = 1.5*10−4, SE = 2.4*10−4, _p_ = 0.53) (see Fig. 1). There was no significant change in anterior

cingulate glutamate concentrations (coefficient = 0.20, SE = 0.60, _p_ = 0.74) (see Fig. 1). MRS quality metrics and checklist are given in Tables 3 and 4. There was a significant

interaction between glutamate and time (coefficient = 3.7*10−4, SE = 1.5*10−4, _p_ = 0.018), reflecting a negative association between Kicer and ACC glutamate at baseline, that was not

present at follow-up (see Fig. 2). This finding is also illustrated by the fact that at baseline there was a significant interaction between patients and controls in the dopamine-glutamate

relationship (estimate = −3.0*10−4, SE = 1.7*10−4, _p_ = 0.03, previously reported [23]). In contrast, where data obtained in patients at follow-up was compared to the same data obtained at

the single timepoint in controls there was no difference between patients and controls in this dopamine-glutamate relationship (estimate = −1.7*10−5, SE = 2.1*10−4, _p_ = 0.93, see Fig. 3).

The interaction between Glx and time was not significant (coefficient = 1.8*10−4, SE = 1.0*10−4, _p_ = 0.077). DISCUSSION We observed normalization of the relationship between striatal Kicer

and anterior cingulate glutamate in people with first episode psychosis following antipsychotic treatment. This change in relationship was significant, and the follow-up dopamine-glutamate

relationship was similar to that observed in healthy controls at baseline. To the best of our knowledge this is the first study to examine relationships between striatal 18F-DOPA Kicer and

anterior cingulate glutamate before and after antipsychotic treatment. Strengths of the study include the fact that the population under study consisted of patients with a first episode

psychosis, and were predominantly antipsychotic free or naïve at baseline. Limitations include a modest sample size and naturalistic antipsychotic treatment. However, all antipsychotics were

prescribed at valid treatment dose, and changes seen in PANSS indicated adequate clinical response in the majority of patients. The lack of placebo group means it is impossible to infer

symptom change being wholly due to antipsychotic treatment,. A further weakness is the lack of follow-up data in the control group. Prior studies have examined changes in each of these

measures separately in similar populations (first episode psychosis/schizophrenia) [17,18,19, 21], though both measures have not been examined together in the same population. Prior studies

show conflicting results, with decreases in anterior cingulate glutamate following antipsychotic treatment suggested in a systematic review of small studies [19] and a relatively large

sample (_n_ = 46) [20], though no change in a relatively large study (_n_ = 45) [21]. A decrease was seen in 18F-DOPA Ki in a sample of 9 people treated with sub-chronic haloperidol [17],

though no change in a larger sample examined by our group, a subsample of which was examined here [18]. It is important to acknowledge the test/re-test reliability of both imaging measures.

Regarding 18F-DOPA PET, inter-rater reliability was measured in 8 healthy controls, with an interclass correlation of 0.843 for Whole Striatum, and mean time between scans was (Mean ± SD

113.6 + /-16 weeks). The reliability of MRS Glu at 3 T has been measured in posterior cingulate cortex (PCC), using PRESS sequence, in 18 individuals (range 1 day–1 week), ICC = 0.8 [39]. As

acknowledged [23], the glutamate signal at 3 T includes a contribution from Glutamnine (10–15%), and there is an inability to differentiate intracellular and extracellular glutamate

concentrations. Similarly, our measure of dopamine synthesis capacity, aromatic acid decarboxylase (AADC) is not the rate-limiting enyme for dopamine synthesis, though remains the best

tracer available, in terms of reliability and validity [25]. By applying CRLB threshold (>20%) as opposed to an absolute threshold, across all subjects, it is conceivable that if

concentrations are lower in one group or time point, this group would have higher CRLBs [40]. However, we found no significant difference in concentrations at different time points, and

therefore this effect is unlikely. By examining the relationship between striatal 18F-DOPA Kicer and anterior cingulate glutamate, we suggest antipsychotic medication may exert effects on

the relationship between these two measures. Specifically, the change in relationship is towards that seen in controls. One model of psychosis pathoetiology proposes that dysregulation of

cortical glutamatergic neurons [4, 41], through impaired GABA-ergic inhibition, leads to disinhibition of excitatory projections to dopamine neuron cell bodies in the midbrain, to stimulate

dopamine neuron firing [41]. There is meta-analytic evidence that antipsychotics may reduce cortical glutamate levels in-vivo, in people with schizophrenia [42], although measures used,

Magnetic Resonance Spectroscopy (MRS), are of total tissue glutamate rather than synaptic glutamate, it remains unclear to what degree this reflect glutamatergic neuronal activity.

Notwithstanding, this could account for an uncoupling of the relationship between cortical glutamate and subcortical dopamine seen in our sample. However, it should be recognized that the

current study does not show causality, and it remains possible that other effects underlie the alterations we report. In-vivo studies utilizing pharmacological manipulation of cortical

glutamatergic activity are needed to disentangle these possibilities [43], as well as pre-clinical models. It should also be recognized that substance misuse, an aetiological factor in

psychosis [44], may have similar effects on these systems, including the effects of cannabis use, decreasing cortical glutamate, seen in an MRS study of people with early psychosis [45]

FUTURE DIRECTIONS This study requires replication in a larger sample, ideally with a control group scanned at both time points. Focusing on specific patient populations, eg those with lower

(relative) dopamine synthesis capacity, may help delineate the interaction with cortical glutamate better, alongside better field strength MRS measures (7 T). It will also be of value to see

how the association highlighted in the current study relates to other interaction effects observed using multimodal imaging [46,47,48,49], and any identified circuits could be further

examined using pre-clinical models. CONCLUSIONS We demonstrated a change in the relationship between measures of striatal dopamine synthesis capacity and anterior cingulate glutamate in

first episode psychosis after antipsychotic treatment, the subsequent relationship being comparable to that seen in healthy controls. REFERENCES * van Rossum JM. The significance of

dopamine-receptor blockade for the mechanism of action of neuroleptic drugs. Arch Int Pharmacodyn Thér. 1966;160:492–4. PubMed  Google Scholar  * Meltzer HY, Stahl SM. The dopamine

hypothesis of schizophrenia: a review. Schizophr Bull. 1976;2:19–76. Article  CAS  PubMed  Google Scholar  * Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III-the

final common pathway. Schizophr Bull. 2009;35:549–62. Article  PubMed  PubMed Central  Google Scholar  * McCutcheon RA, Krystal JH, Howes OD. Dopamine and glutamate in schizophrenia:

biology, symptoms and treatment. World Psychiatry. 2020;19:15–33. Article  PubMed  PubMed Central  Google Scholar  * Seeman P, Lee T. Antipsychotic drugs: direct correlation between clinical

potency and presynaptic action on dopamine neurons. Science 1975;188:1217–9. Article  CAS  PubMed  Google Scholar  * Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts

clinical and pharmacological potencies of antischizophrenic drugs. Science 1976;192:481–3. Article  CAS  PubMed  Google Scholar  * Farde L, Nordström AL, Wiesel FA, Pauli S, Halldin C,

Sedvall G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal

side effects. Arch Gen Psychiatry. 1992;49:538–44. Article  CAS  PubMed  Google Scholar  * Kapur S. Relationship between dopamine D2 occupancy, clinical response, and side effects: a

double-blind PET study of first-episode Schizophrenia. Am J Psychiatry. 2000;157:514–20. Article  CAS  PubMed  Google Scholar  * Garbutt JC, van Kammen DP. The interaction between GABA and

dopamine: implications for schizophrenia. Schizophr Bull. 1983;9:336–53. Article  CAS  PubMed  Google Scholar  * Kapur S, Remington G. Serotonin-dopamine interaction and its relevance to

schizophrenia. Am J Psychiatry. 1996;153:466–76. Article  CAS  PubMed  Google Scholar  * Covey DP, Mateo Y, Sulzer D, Cheer JF, Lovinger DM. Endocannabinoid modulation of dopamine

neurotransmission. Neuropharmacology 2017;124:52–61. Article  CAS  PubMed  PubMed Central  Google Scholar  * Carr DB, Sesack SR. Projections from the rat prefrontal cortex to the ventral

tegmental area: target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons. J Neurosci. 2000;20:3864–73. Article  CAS  PubMed  PubMed Central  Google Scholar

  * Samaha A-N, Seeman P, Stewart J, Rajabi H, Kapur S. ‘Breakthrough’ dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neurosci J Soc

Neurosci. 2007;27:2979–86. Article  CAS  Google Scholar  * McLoughlin GA, Ma D, Tsang TM, Jones DNC, Cilia J, Hill MD, et al. Analyzing the effects of psychotropic drugs on metabolite

profiles in rat brain using 1H NMR spectroscopy. J Proteome Res. 2009;8:1943–52. Article  CAS  PubMed  Google Scholar  * Kokkinou M, Ashok AH, Howes OD. The effects of ketamine on

dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders. Mol Psychiatry. 2018;23:59–69. Article  CAS  PubMed  Google Scholar  * Rogeau A, Nordio G,

Veronese M, Brown K, Nour MM, Osugo M, et al. The relationship between glutamate, dopamine, and cortical gray matter: a simultaneous PET-MR study. Mol Psychiatry. 2022;27:3493–3500. Article

  CAS  PubMed  PubMed Central  Google Scholar  * Gründer G, Vernaleken I, Müller MJ, Davids E, Heydari N, Buchholz HG, et al. Subchronic haloperidol downregulates dopamine synthesis capacity

in the brain of schizophrenic patients in vivo. Neuropsychopharmacology 2003;28:787–94. Article  PubMed  Google Scholar  * Jauhar S, Veronese M, Nour MM, Rogdaki M, Hathway P, Natesan S, et

al. The effects of antipsychotic treatment on presynaptic dopamine synthesis capacity in first-episode Psychosis: a positron emission tomography study. Biol Psychiatry. 2019;85:79–87.

Article  CAS  PubMed  Google Scholar  * Egerton A, Bhachu A, Merritt K, McQueen G, Szulc A, McGuire P. Effects of antipsychotic administration on brain glutamate in schizophrenia: a

systematic review of longitudinal (1)H-MRS studies. Front Psychiatry. 2017;8:66. Article  PubMed  PubMed Central  Google Scholar  * Egerton A, Broberg BV, Van Haren N, Merritt K, Barker GJ,

Lythgoe DJ, et al. Response to initial antipsychotic treatment in first episode psychosis is related to anterior cingulate glutamate levels: a multicentre 1H-MRS study (OPTiMiSE). Mol

Psychiatry. 2018;23:2145–55. Article  CAS  PubMed  Google Scholar  * Kraguljac NV, Morgan CJ, Reid MA, White DM, Jindal RD, Sivaraman S, et al. A longitudinal magnetic resonance spectroscopy

study investigating effects of risperidone in the anterior cingulate cortex and hippocampus in schizophrenia. Schizophr Res. 2019. https://doi.org/10.1016/j.schres.2018.12.028. * Gleich T,

Deserno L, Lorenz RC, Boehme R, Pankow A, Buchert R, et al. Prefrontal and striatal glutamate differently relate to striatal dopamine: potential regulatory mechanisms of striatal presynaptic

dopamine function? J Neurosci. 2015;35:9615–21. Article  CAS  PubMed  PubMed Central  Google Scholar  * Jauhar S, McCutcheon R, Borgan F, Veronese M, Nour M, Pepper F, et al. The

relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study. Lancet

Psychiatry. 2018;5:816–23. Article  PubMed  PubMed Central  Google Scholar  * Organization WH. The ICD-10 classification of mental and behavioural disorders: clinical descriptions and

diagnostic guidelines. World Health Organization; 1992. * Jauhar S, Nour MM, Veronese M, Rogdaki M, Bonoldi I, Azis M, et al. A test of the transdiagnostic dopamine hypothesis of psychosis

using positron emission tomographic imaging in bipolar affective disorder and Schizophrenia. JAMA Psychiatry. 2017;74:1206–13. Article  PubMed  PubMed Central  Google Scholar  * Sheehan DV,

Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (MINI): the development and validation of a structured diagnostic psychiatric

interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59:22–33. PubMed  Google Scholar  * Taylor DM, Barnes TRE, Young AH. The Maudsley prescribing guidelines in psychiatry. 13th edn.

Hoboken, NJ: Wiley-Blackwell; 2018. * Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJM, Birnbaum ML, et al. Treatment-resistant Schizophrenia: Treatment Response and

Resistance in Psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. Am J Psychiatry. 2016;174:216–29. Article  PubMed  PubMed Central  Google Scholar  *

Andreasen NC, Pressler M, Nopoulos P, Miller D, Ho B-C. Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs. Biol Psychiatry.

2010;67:255–62. Article  CAS  PubMed  Google Scholar  * Leucht S, Samara M, Heres S, Patel MX, Woods SW, Davis JM. Dose equivalents for second-generation antipsychotics: the minimum

effective dose method. Schizophr Bull. 2014;40:314–26. Article  PubMed  PubMed Central  Google Scholar  * Jauhar S, Veronese M, Rogdaki M, Bloomfield M, Natesan S, Turkheimer F, et al.

Regulation of dopaminergic function: an [18F]-DOPA PET apomorphine challenge study in humans. Transl Psychiatry. 2017;7:e1027. Article  CAS  PubMed  PubMed Central  Google Scholar  * SPM.

Statistical parametric mapping. 2016. http://www.fil.ion.ucl.ac.uk/spm/. * Egerton A, Mehta MA, Montgomery AJ, Lappin JM, Howes OD, Reeves SJ, et al. The dopaminergic basis of human

behaviors: a review of molecular imaging studies. Neurosci Biobehav Rev. 2009;33:1109–32. Article  CAS  PubMed  PubMed Central  Google Scholar  * Martinez D, Narendran R, Foltin RW,

Slifstein M, Hwang D-R, Broft A, et al. Amphetamine-induced dopamine release: markedly blunted in cocaine dependence and predictive of the choice to self-administer cocaine. Am J Psychiatry.

2007;164:622–9. Article  PubMed  Google Scholar  * Veronese M, Santangelo B, Jauhar S, D'Ambrosio E, Demjaha A, Salimbeni H, et al. A potential biomarker for treatment stratification

in psychosis: evaluation of an [18 F] FDOPA PET imaging approach. Neuropsychopharmacology. 2021;46:1122–1132. https://doi.org/10.1038/s41386-020-00866-7. Article  CAS  PubMed  Google Scholar

  * LCModel’s home page. http://s-provencher.com/pages/lcmodel.shtml. Accessed 12 September 2016. * StataCorp. Stata statistical software: release 13. College Station, TX: StataCorp LP;

2013. * The R Foundation. R: The R project for statistical computing. https://www.r-project.org/. Accessed 24 February 2018. * Baeshen A, Wyss PO, Henning A, O’Gorman RL, Piccirelli M,

Kollias S, et al. Test–retest reliability of the Brain Metabolites GABA and Glx With JPRESS, PRESS, and MEGA-PRESS MRS Sequences in vivo at 3T. J Magn Reson Imaging. 2020;51:1181–91. Article

  PubMed  Google Scholar  * Kreis R. The trouble with quality filtering based on relative Cramér-Rao lower bounds. Magn Reson Med. 2016;75:15–18. Article  PubMed  Google Scholar  *

McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia—An overview. JAMA Psychiatry. 2020;77:201–10. Article  PubMed  Google Scholar  * Merritt K, McGuire PK, Egerton A, 1H-MRS in

Schizophrenia Investigators, Aleman A, Block W, et al. Association of age, antipsychotic medication, and symptom severity in Schizophrenia with proton magnetic resonance spectroscopy brain

glutamate level: a mega-analysis of individual participant-level data. JAMA Psychiatry. 2021. https://doi.org/10.1001/jamapsychiatry.2021.0380. * Pillinger T, Rogdaki M, McCutcheon RA,

Hathway P, Egerton A, Howes OD. Altered glutamatergic response and functional connectivity in treatment resistant schizophrenia: the effect of riluzole and therapeutic implications.

Psychopharmacol (Berl). 2019;236:1985–97. Article  CAS  Google Scholar  * Jauhar S, Johnstone M, McKenna PJ. Schizophrenia. Lancet Lond Engl. 2022;399:473–86. Article  CAS  Google Scholar  *

Rigucci S, Xin L, Klauser P, Baumann PS, Alameda L, Cleusix M, et al. Cannabis use in early psychosis is associated with reduced glutamate levels in the prefrontal cortex. Psychopharmacol

(Berl). 2018;235:13–22. Article  CAS  Google Scholar  * McCutcheon RA, Marques TR, Howes OD. Schizophrenia—An overview. JAMA Psychiatry. 2019;77:201–10. Article  Google Scholar  * McCutcheon

RA, Nour MM, Dahoun T, Jauhar S, Pepper F, Expert P, et al. Mesolimbic dopamine function is related to salience network connectivity: an integrative positron emission tomography and

magnetic resonance study. Biol Psychiatry. 2019;85:368–78. Article  CAS  PubMed  PubMed Central  Google Scholar  * Limongi R, Jeon P, Mackinley M, Das T, Dempster K, Théberge J, et al.

Glutamate and dysconnection in the salience network: neurochemical, effective-connectivity, and computational evidence in schizophrenia. Biol Psychiatry. 2020;88:273–81. Article  CAS  PubMed

  Google Scholar  * McCutcheon RA, Pillinger T, Rogdaki M, Bustillo J, Howes OD. Glutamate connectivity associations converge upon the salience network in schizophrenia and healthy controls.

Transl Psychiatry. 2021;11:322. Article  CAS  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS The authors would like to thank all the patients and their family

members who facilitated this research, as well as Drs Paul Morrison and Nikola Rahamann, the Early Intervention teams in South London and Maudsley NHS Foundation Trust (COAST, STEP, LEO and

LEIS) and CNWL who facilitated recruitment to the study. FUNDING SJ, JMS, AE, FT, PM and ODH are supported by the National Institute for Health Research Biomedical Research Centre at South

London, Maudsley National Health Service Foundation Trust, King’s College London, and SJ by a JMAS (John, Margaret, Alfred, and Stewart) Sim Fellowship from the Royal College of Physicians,

Edinburgh. MV is supported by MIUR, Italian Ministry for Education, under the initiatives “Departments of Excellence” (Law 232/2016) and by Wellcome Trust Digital Award (no. 215747/Z/19/Z).

RM’s work is funded by a Wellcome Trust Clinical Research Career Development (224625/Z/21/Z). FB became an employee at COMPASS Pathways plc after the completion of this work. This work is

unrelated to COMPASS Pathways plc. For the purpose of open access, this paper has been published under the creative common licence (CC-BY). This study was funded by Medical Research

Council-UK (MC_U120097115; MR/W005557/1 and MR/V013734/1), and Wellcome Trust (no. 094849/Z/10/Z) grants to ODH and the National Institute for Health Research (NIHR) Biomedical Research

Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS/NIHR or the Department

of Health. SJ has received honoraria for educational lectures given for Boehringer Ingelheim, Janssen, Sunovion, and King’s College London has received honoraria for lectures SJ has given

for Lundbeck. RM has received speaker consultancy fees from Karuna, Janssen, Boehringer Ingelheim, and Otsuka, and is director of a company that hosts psychotropic prescribing decision

tools. MV hold a patent application for the use of dopamine imaging as a prognostic tool in mental health (WO2021111116). FB reports no biomedical, financial interests or potential conflicts

of interest. MN reports no biomedical, financial interests or potential conflicts of interest. MR reports no biomedical, financial interests or potential conflicts of interest. FP reports

no biomedical, financial interests or potential conflicts of interest. In the last 3 years, JMS has been principal investigator or sub-investigator on studies sponsored by Takeda, Janssen,

and Lundbeck Plc. AE reports no biomedical, financial interests or potential conflicts of interest. GV reports no biomedical, financial interests or potential conflicts of interest. FT

reports no biomedical, financial interests or potential conflicts of interest. PKM reports no biomedical, financial interests or potential conflicts of interest. ODH is a part-time employee

and stock holder of Lundbeck A/s. He has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Angellini, Autifony, Biogen,

Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche and Viatris/ Mylan. ODH has a patent for the

use of dopaminergic imaging. AUTHOR INFORMATION Author notes * These authors contributed equally: Sameer Jauhar, Robert A. McCutcheon. AUTHORS AND AFFILIATIONS * Psychological Medicine,

Institute of Psychiatry, Psychology and Neuroscience, King’s College, London, UK Sameer Jauhar * Department of Psychiatry, University of Oxford, Oxford, UK Robert A. McCutcheon & Philip

K. McGuire * Oxford Health NHS Foundation Trust, Oxford, UK Robert A. McCutcheon * Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College,

London, UK Robert A. McCutcheon, Faith Borgan, Maria Rogdaki, Fiona Pepper, Alice Egerton & Oliver D. Howes * Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and

Neuroscience, King’s College, London, UK Mattia Veronese & Federico Turkheimer * Max Planck UCL Centre for Computational Psychiatry and Ageing Research, Berlin, Germany Matthew Nour *

Department of Neuroscience and Imaging, University of Sussex, Brighton and Hove, UK James M. Stone * Department of Biostatistics, Institute of Psychiatry, Psychology and Neuroscience, King’s

College, London, UK George Vamvakas * MRC London Institute of Medical Sciences, Imperial College, London, UK Oliver D. Howes * H Lundbeck A/s, St Albans, UK Oliver D. Howes Authors * Sameer

Jauhar View author publications You can also search for this author inPubMed Google Scholar * Robert A. McCutcheon View author publications You can also search for this author inPubMed 

Google Scholar * Mattia Veronese View author publications You can also search for this author inPubMed Google Scholar * Faith Borgan View author publications You can also search for this

author inPubMed Google Scholar * Matthew Nour View author publications You can also search for this author inPubMed Google Scholar * Maria Rogdaki View author publications You can also

search for this author inPubMed Google Scholar * Fiona Pepper View author publications You can also search for this author inPubMed Google Scholar * James M. Stone View author publications

You can also search for this author inPubMed Google Scholar * Alice Egerton View author publications You can also search for this author inPubMed Google Scholar * George Vamvakas View author

publications You can also search for this author inPubMed Google Scholar * Federico Turkheimer View author publications You can also search for this author inPubMed Google Scholar * Philip

K. McGuire View author publications You can also search for this author inPubMed Google Scholar * Oliver D. Howes View author publications You can also search for this author inPubMed Google

Scholar CONTRIBUTIONS SJ, RM and ODH conceived the initial plan for the manuscript. MV and FB contributed to analysis of imaging data. MN, MR and FP collected clinical and imaging data.

JMS, AE, FT and PKM contributed to interpretation of the imaging findings. GV consulted and conducted statistical analyses regarding modelling of the data. SJ, RM and ODH wrote the first

draft of the manuscript, and all authors contributed to revisions and interpretation of findings. CORRESPONDING AUTHOR Correspondence to Sameer Jauhar. ETHICS DECLARATIONS COMPETING

INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and

institutional affiliations. SUPPLEMENTARY INFORMATION SUPPLSUPPLEMENTARY MATERIAL RIGHTS AND PERMISSIONS OPEN ACCESS This article is licensed under a Creative Commons Attribution 4.0

International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the

source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative

Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by

statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit

http://creativecommons.org/licenses/by/4.0/. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Jauhar, S., McCutcheon, R.A., Veronese, M. _et al._ The relationship between

striatal dopamine and anterior cingulate glutamate in first episode psychosis changes with antipsychotic treatment. _Transl Psychiatry_ 13, 184 (2023).

https://doi.org/10.1038/s41398-023-02479-2 Download citation * Received: 16 December 2021 * Accepted: 15 May 2023 * Published: 31 May 2023 * DOI: https://doi.org/10.1038/s41398-023-02479-2

SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to

clipboard Provided by the Springer Nature SharedIt content-sharing initiative