Bupropion has been used as an antidepressant for over 20 years, though its licence for such use varies and it is typically a third-or fourth-line agent. It has a unique pharmacology, inhibiting the reuptake of noradrenaline and dopamine, potentially providing pharmacological augmentation to more common antidepressants such as selective serotonergic reuptake inhibitors (SSRIs). This systematic review and meta-analysis identified 51 studies, dividing into four categories: bupropion as a sole antidepressant, bupropion coprescribed with another antidepressant, bupropion in 'other' populations (e.g. bipolar depression, elderly populations) and primary evaluation of side effects. Methodologically more robust trials support the superiority of bupropion over placebo, and most head-to-head antidepressant trials showed an equivalent effectiveness, though some of these are hindered by a lack of a placebo arm. Most work on the coprescribing of bupropion with another antidepressant supports an additional effect, though many are open-label trials. Several large multi-medication trials, most notably STAR*D, also support a therapeutic role for bupropion; in general, it demonstrated similar effectiveness to other medications, though this literature highlights the generally low response rates in refractory cohorts. Effectiveness has been shown in 'other' populations, though there is an overall dearth of research. Bupropion is generally well tolerated, it has very low rates of sexual dysfunction, and is more likely to cause weight loss than gain. Our findings support the use of bupropion as a sole or coprescribed antidepressant, particularly if weight gain or sexual dysfunction are, or are likely to be, significant problems. However there are notable gaps in the literature, including less information on treatment naïve and first presentation depression, particularly when one considers the ever-reducing rates of response in more refractory illness. There are some data to support bupropion targeting specific symptoms, but insufficient information to reliably inform such prescribing, and it remains uncertain whether bupropion pharmacodynamically truly augments other drugs.

Parvalbumin interneurons are fast-spiking GABAergic neurons that provide inhibitory control of cortical and subcortical circuits and are thought to be a key locus of the pathophysiology underlying schizophrenia. In view of the contradictory results regarding the nature of parvalbumin post-mortem findings in schizophrenia, we conducted a quantitative meta-analysis of the data on parvalbumin cell density and parvalbumin mRNA levels in pre-frontal regions in the brains of patients with schizophrenia (n = 274) compared with healthy controls (n = 275). The results suggest that parvalbumin interneurons are reduced in density in the frontal cortex of patients with schizophrenia (Hedges’ g = − 0.27; p = 0.03) and there is a non-significant reduction in parvalbumin mRNA levels (g = − 0.44; p = 0.12). However, certain methodological issues need to be considered in interpreting such results and are discussed in more detail. A meta-regression was conducted for post-mortem interval and year of publication as covariates which were both non-significant, except in the mRNA meta-analysis where post-mortem interval was found to be significant. Overall our findings provide tentative support for the hypothesis that the GABAergic system is deficient in schizophrenia and that parvalbumin-containing interneurons offer a potential target for treatment. However, further well-controlled studies that examine multiple regions and layers are warranted to determine whether parvalbumin alterations are region or layer specific and to test the robustness of the findings further.Electronic supplementary materialThe online version of this article (10.1007/s00702-019-02080-2) contains supplementary material, which is available to authorized users.

Background It has been hypothesized that dopamine function in schizophrenia exhibits heterogeneity in excess of that seen in the general population. However, this hypothesis has never been systematically tested. Method We employed meta-analysis of variance to investigate inter-individual variability of striatal dopaminergic function in patients with schizophrenia and healthy controls. We included 65 studies reporting molecular imaging measures of dopamine synthesis or release capacities, D2/3 receptor (D2/3R) or transporter (DAT) availabilities, or synaptic dopamine levels, in 983 patients and 968 controls. Variability differences were quantified using variability ratio (VR) and coefficient of variation ratio. Results Inter-individual variability of striatal D2/3R (VR=1.26, p<.0001) and DAT availabilities (VR=1.31, p=.01), and synaptic dopamine levels (VR=1.38, p=.045), but not dopamine synthesis (VR=1.12, p=.13) or release (VR=1.08, p=.70) capacities, were significantly greater in patients.. Findings were robust to variability measure. Mean dopamine synthesis (g=0.65, p=.004) and release (g=0.66, p=.03) capacities, as well as synaptic levels (g=0.78, p=.0006) were greater in patients overall, but mean synthesis capacity did not differ relative to controls in treatment resistant patients (p>0.3). Mean D2/3R (g=0.17, p=.14) and DAT (g=-0.20, p=.28) availabilities did not differ between groups. Conclusions Our findings demonstrate significant heterogeneity of striatal dopamine function in schizophrenia. They suggest that while elevated dopamine synthesis and release capacities may be core features of the disorder, altered D2/3R

A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABA A Rs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABA A Rs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABA A Rs are altered in vivo or related to symptoms. We investigated α5-GABA A Rs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [ 11 C]Ro15-4513 PET imaging in a cross-sectional, case-control study design. Thirty-one schizophrenia patients (n = 10 antipsychotic free) and twenty-nine matched healthy controls underwent a [ 11 C]Ro15-4513 PET scan and MRI. The α5 subtype GABA-A receptor availability was indexed using [ 11 C]Ro15-4513 PET imaging. Dynamic PET data were analyzed using the two-tissue compartment model with an arterial plasma input function and total volume of distribution (V T ) as the outcome measure. Symptom severity was assessed using the PANSS scale. There was significantly lower [11C] Ro15-4513 V T in the hippocampus of antipsychotic-free patients, but not in medicated patients (p = 0.64), relative to healthy controls (p < 0.05; effect size = 1.4). There was also a significant positive correlation between [ 11 C]Ro15-4513 V T and total PANSS score in antipsychotic-free patients (r = 0.72; p = 0.044). The results suggest that antipsychotic-free patients with schizophrenia have lower α5-GABAARs levels in the hippocampus, consistent with the hypothesis that GABA hypofunction underlies the pathophysiology of the disorder.

Abnormalities in glutamate neurotransmission are linked to psychotic symptoms and cognitive dysfunction in schizophrenia. magnetic resonance spectroscopy (MRS) provides an acceptable means of measuring glutamate in the human brain but findings from patient studies at conventional magnetic field strength show considerable heterogeneity. Ultra-high-field MRS offers greater precision in glutamate measurement, particularly in delineation of glutamate from its precursor and metabolite, glutamine. This study aimed to use high-field (7 T) MRS to measure concentrations of glutamate and glutamine in three brain regions, anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC) and putamen (PUT), in young men with early psychosis. MRS was performed in 17 male participants with early psychosis and 18 healthy age-matched controls. Neurometabolite levels were calculated with unsuppressed water signal as the reference and corrected for individual grey matter, white matter and cerebrospinal fluid concentration. Cognitive function was measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Compared to controls, patients with early psychosis had lower concentrations of glutamate and glutamine in ACC. No differences were apparent in the DLPFC and PUT. In patients with early psychosis, there was a highly significant correlation between glutamate concentration in ACC and performance on the BACS, though the numbers available for this analysis were small. Our finding of lower glutamate levels in ACC in patients with schizophrenia is consistent with a recent meta-analysis of 7 T studies and suggests that this abnormality is present in both patients with early psychosis and those with longer-established illness. The possible link between ACC glutamate and cognitive performance requires replication in larger studies.