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Meta-Analysis
, 39 (1), 33-42

Striatal Presynaptic Dopamine in Schizophrenia, Part II: Meta-Analysis of [(18)F/(11)C]-DOPA PET Studies

Affiliations
Meta-Analysis

Striatal Presynaptic Dopamine in Schizophrenia, Part II: Meta-Analysis of [(18)F/(11)C]-DOPA PET Studies

Paolo Fusar-Poli et al. Schizophr Bull.

Abstract

Background: Alterations in striatal dopamine neurotransmission are central to the emergence of psychotic symptoms and to the mechanism of action of antipsychotics. Although the functional integrity of the presynaptic system can be assessed by measuring striatal dopamine synthesis capacity (DSC), no quantitative meta-analysis is available.

Methods: Eleven striatal (caudate and putamen) [(11)C/(18)F]-DOPA positron emission tomography studies comparing 113 patients with schizophrenia and 131 healthy controls were included in a quantitative meta-analysis of DSC. Demographic, clinical, and methodological variables were extracted from each study or obtained from the authors and tested as covariates. Hedges' g was used as a measure of effect size in Comprehensive Meta-Analysis. Publication bias was assessed with funnel plots and Egger's intercept. Heterogeneity was addressed with the Q statistic and I(2) index.

Results: Patients and controls were well matched in sociodemographic variables (P > .05). Quantitative evaluation of publication bias was nonsignificant (P = .276). Heterogeneity across study was modest in magnitude and statistically nonsignificant (Q = 19.19; P = .078; I (2) = 39.17). Patients with schizophrenia showed increased striatal DSC as compared with controls (Hedges' g = 0.867, CI 95% from 0.594 to 1.140, Z = 6.222, P < .001). The DSC schizophrenia/control ratio showed a relatively homogenous elevation of around 14% in schizophrenic patients as compared with controls. DSC elevation was regionally confirmed in both caudate and putamen. Controlling for potential confounders such as age, illness duration, gender, psychotic symptoms, and exposure to antipsychotics had no impact on the results. Sensitivity analysis confirmed robustness of meta-analytic findings.

Conclusions: The present meta-analysis showed consistently increased striatal DSC in schizophrenia, with a 14% elevation in patients as compared with healthy controls.

Figures

Fig. 1.
Fig. 1.
Molecular basis of presynaptic dopamine (DA) regulation. The majority of circulating L-tyrosine (Tyr) originates from dietary sources, but small amounts are derived from hydroxylation of phenylalanine by the liver. Blood-borne Tyr is taken up into the brain by a low-affinity amino acid transport system and subsequently from brain extracellular fluid into dopaminergic neurons by high- and low-affinity amino acid transporters. In the presynaptic dopaminergic neuron, Tyr is converted to L-3,4-dihydroxyphenylalanine (l-DOPA) by the enzyme tyrosine hydroxylase (TH). TH does so using tetrahydrobiopterin (bh4) and dihydrobiopterin (bh2) as coenzymes and dihydrobiopterin reductase (DDR) with NADP+/NADH. TH is a rate-limiting enzyme in DA synthesis and is inhibited by its own substrate. DA cannot enter the brain to an appreciable degree but the blood-brain barrier contains the large (L)-type amino acid transporter (l-AAT), which is able to transport the DA precursor, l-DOPA, and its radiolabelled analogs. Subsequently, DOPA decarboxylase or aromatic amino acid decarboxylase (AAADC) converts l-DOPA to DA (3) using pyridoxal phosphate (PP). DA is then transported and concentrated from the cytoplasm to specialized storage vesicles by the vesicular monoamine transporter (VMAT). Most DA is packaged in vesicles from which it is released on the arrival of action potentials. This process relies on the activity of an ATP-dependent vesicular proton pump (H+-ATPase) using ATP formed during oxidative phosphorylation (Ox Phos) at local mitochondria. Synaptic DA release is regulated by tonic activity and bursts by a large number of receptors and second messengers at the level of the dendrites. The secretory response at the neuronal terminal is regulated by the complex interplay of DA autoreceptors (D2) and heterosynaptic receptors (metabotropic glutamate, mGlu; nicotinic and muscarinic acetylcholine, nACh and mAChR; GABA and opiate, K). Their second messengers modulate different pathways and ultimately the voltage-gated Ca++ channels, affecting the targeting of the vescicles to the active zone of the presynaptic membrane, docking, fusion, release of the vescicular content, retrieval by endocytosis, and refilling with the neurotransmitter. After release, DA is rapidly taken up by dopamine transporters (DAT) on the terminal regulating extracellular dopamine homeostasis. Cytosolic DA is catabolized by monoamine oxidase (MAO) and aldehyde dehydrogenase (AD) to 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is exported from the neuron and methylated by catecholamine methyl transferase (COMT) to homovanillic acid (HVA). Extracellular DA catabolism is regulated by COMT, which with extraneuronal MAO and AD produce again HVA. The overall dopamine synthesis capacity (DSC) reflects the complex interplay of the above synthesis, storage, release, and reuptake processes.
Fig. 2.
Fig. 2.
Meta-analysis of striatal dopamine synthesis capacity (DSC) in schizophrenia employing random effect models (test for heterogeneity Q = 19.19; P = .078; I 2 = 39.17). Positive values of Hedges’ g indicate greater DSC in patients as compared with controls.
Fig. 3.
Fig. 3.
Meta-regression of antipsychotic exposure (proportion % of drug naive subjects) on striatal dopamine synthesis capacity point estimates (Hedges’ g). Circle size reflects the weight a study obtained in the meta-regression. Note that excluding the potential outliers did not affect statistical significance (P > .05).

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