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Tremor and Other Hyperkinetic Movements... 2024Tardive Dyskinesia (TD) is a neurological disorder characterized by involuntary movements, often caused by dopamine receptor antagonists. Vesicular Monoamine Transporter... (Comparative Study)
Comparative Study Review
BACKGROUND
Tardive Dyskinesia (TD) is a neurological disorder characterized by involuntary movements, often caused by dopamine receptor antagonists. Vesicular Monoamine Transporter 2 (VMAT2) inhibitors, such as valbenazine and deutetrabenazine, have emerged as promising therapies for TD and several clinical trials have shown their efficacy. This study aims to compare the efficacy and safety profile of VMAT2 inhibitors, focusing on a recent trial conducted in the Asian population.
METHODS
We reviewed the PubMed, Cochrane Library, Embase database, and clinicaltrials.gov between January 2017 and October 2023, using the keywords "tardive dyskinesia" AND ("valbenazine" [all fields] OR " deutetrabenazine " [all fields]) AND "clinical trial". The reviewed articles were studied for efficacy and side effects.
RESULTS
An initial search yielded 230 articles, of which 104 were duplicates. Following the title and abstract screening, 25 additional articles were excluded. A full-text review resulted in the exclusion of 96 more articles. Ultimately, four double-blind clinical trials met the inclusion criteria. The deutetrabenazine studies demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores compared to placebo, with no difference in adverse events. The valbenazine studies showed favorable results in reducing TD symptoms and were well-tolerated.
DISCUSSION
The studies reviewed in this analysis underscore the potential of deutetrabenazine and valbenazine as valuable treatment options for TD in diverse populations. Both medications demonstrated significant improvements in AIMS scores, suggesting their effectiveness in managing TD symptoms. Additionally, they exhibited favorable safety profiles, with low rates of serious adverse events and no significant increase in QT prolongation, parkinsonism, suicidal ideation, or mortality.
CONCLUSION
The studies reviewed highlight the promising efficacy and tolerability of deutetrabenazine and valbenazine as treatments for Tardive Dyskinesia, providing new hope for individuals affected by this challenging condition.
Topics: Humans; Randomized Controlled Trials as Topic; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins
PubMed: 38497033
DOI: 10.5334/tohm.842 -
Psychopharmacology Feb 2024Dopamine antagonists induce dopamine receptor supersensitivity. This may manifest in late-appearing movement disorders (tardive dyskinesia (TD). VMAT-2 inhibitors reduce... (Meta-Analysis)
Meta-Analysis Review
RATIONALE
Dopamine antagonists induce dopamine receptor supersensitivity. This may manifest in late-appearing movement disorders (tardive dyskinesia (TD). VMAT-2 inhibitors reduce dopaminergic transmission but have limited activity at postsynaptic receptors and so may have antipsychotic activity with lower risk of tardive dyskinesia.
METHODS
We conducted a systematic database search from inception to September 2022 for articles describing the use of VMAT-2 inhibitors in psychosis. Inclusion criteria were as follows: Population: adults diagnosed with psychosis or schizophrenia; Intervention: treatment with tetrabenazine, deutetrabenazine or valbenazine; Comparison: comparison with placebo or/and antipsychotic drug; Outcomes: with efficacy outcomes (e.g. Brief Psychiatric Rating Scale (BPRS) change or clinician assessment) and adverse effects ratings (e.g. rating scale or clinician assessment or dropouts); and Studies: in randomised controlled trials and non-randomised studies.
RESULTS
We identified 4892 records relating to VMAT-2 inhibitor use of which 5 (173 participants) met our a priori meta-analysis inclusion criteria. VMAT-2 inhibitors were more effective than placebo for the outcome 'slight improvement' (risk ratio (RR) = 1.77 (95% CI 1.03, 3.04)) but not for 'moderate improvement' (RR 2.81 (95% CI 0.27, 29.17). VMAT-2 inhibitors were as effective as active comparators on both measures for-'slight improvement' (RR 1.05 (95% CI 0.6, 1.81)) and 'moderate improvement' (RR 1.11 (95% CI 0.51, 2.42). Antipsychotic efficacy was also suggested by a narrative review of 37 studies excluded from the meta-analysis.
CONCLUSIONS
VMAT-2 inhibitors may have antipsychotic activity and may offer promise for treatment of psychosis with the potential for a reduced risk of TD.
Topics: Adult; Humans; Antipsychotic Agents; Psychotic Disorders; Schizophrenia; Tardive Dyskinesia; Tetrabenazine; Vesicular Monoamine Transport Proteins
PubMed: 38238580
DOI: 10.1007/s00213-023-06488-3 -
Journal of Psychopharmacology (Oxford,... Nov 2023Major depressive disorder (MDD) is a leading cause of global disability. Several lines of evidence implicate the dopamine system in its pathophysiology. However, the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Major depressive disorder (MDD) is a leading cause of global disability. Several lines of evidence implicate the dopamine system in its pathophysiology. However, the magnitude and consistency of the findings are unknown. We address this by systematically reviewing in vivo imaging evidence for dopamine measures in MDD and meta-analysing these where there are sufficient studies.
METHODS
Studies investigating the dopaminergic system using positron emission tomography or single photon emission computed tomography in MDD and a control group were included. Demographic, clinical and imaging measures were extracted from each study, and meta-analyses and sensitivity analyses were conducted.
RESULTS
We identified 43 studies including 662 patients and 801 controls. Meta-analysis of 38 studies showed no difference in mean or mean variability of striatal D receptor availability ( = 0.06, = 0.620), or combined dopamine synthesis and release capacity ( = 0.19, = 0.309). Dopamine transporter (DAT) availability was lower in the MDD group in studies using DAT selective tracers ( = -0.56, = 0.006), but not when tracers with an affinity for serotonin transporters were included ( = -0.21, = 0.420). Subgroup analysis showed greater dopamine release ( = 0.49, = 0.030), but no difference in dopamine synthesis capacity ( = -0.21, = 0.434) in the MDD group. Striatal D receptor availability was lower in patients with MDD in two studies.
CONCLUSIONS
The meta-analysis indicates striatal DAT availability is lower, but D receptor availability is not altered in people with MDD compared to healthy controls. There may be greater dopamine release and lower striatal D receptors in MDD, although further studies are warranted. We discuss factors associated with these findings, discrepancies with preclinical literature and implications for future research.
Topics: Humans; Dopamine; Depressive Disorder, Major; Tomography, Emission-Computed, Single-Photon; Positron-Emission Tomography; Receptors, Dopamine D2; Dopamine Plasma Membrane Transport Proteins
PubMed: 37811803
DOI: 10.1177/02698811231200881 -
Obesity Reviews : An Official Journal... Nov 2023This systematic review collates studies of dietary or bariatric surgery interventions for obesity using positron emission tomography and single-photon emission computed... (Review)
Review
Effects of bariatric surgery and dietary interventions for obesity on brain neurotransmitter systems and metabolism: A systematic review of positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies.
This systematic review collates studies of dietary or bariatric surgery interventions for obesity using positron emission tomography and single-photon emission computed tomography. Of 604 publications identified, 22 met inclusion criteria. Twelve studies assessed bariatric surgery (seven gastric bypass, five gastric bypass/sleeve gastrectomy), and ten dietary interventions (six low-calorie diet, three very low-calorie diet, one prolonged fasting). Thirteen studies examined neurotransmitter systems (six used tracers for dopamine DRD2/3 receptors: two each for C-raclopride, F-fallypride, I-IBZM; one for dopamine transporter, I-FP-CIT; one used tracer for serotonin 5-HT receptor, F-altanserin; two used tracers for serotonin transporter, C-DASB or I-FP-CIT; two used tracer for μ-opioid receptor, C-carfentanil; one used tracer for noradrenaline transporter, C-MRB); seven studies assessed glucose uptake using F-fluorodeoxyglucose; four studies assessed regional cerebral blood flow using O-H O (one study also used arterial spin labeling); and two studies measured fatty acid uptake using F-FTHA and one using C-palmitate. The review summarizes findings and correlations with clinical outcomes, eating behavior, and mechanistic mediators. The small number of studies using each tracer and intervention, lack of dietary intervention control groups in any surgical studies, heterogeneity in time since intervention and degree of weight loss, and small sample sizes hindered the drawing of robust conclusions across studies.
Topics: Humans; Positron-Emission Tomography; Tomography, Emission-Computed, Single-Photon; Bariatric Surgery; Brain; Obesity; Neurotransmitter Agents
PubMed: 37699864
DOI: 10.1111/obr.13620 -
Biomedicines Aug 2023Major Depressive Disorder (MDD) is a disabling and particularly persistent mental disorder that is considered to be a priority public health problem. The active human... (Review)
Review
Major Depressive Disorder (MDD) is a disabling and particularly persistent mental disorder that is considered to be a priority public health problem. The active human dopamine transporter (DAT), which is encoded by the gene, regulates the dopamine concentration in the synaptic cleft. In this sense, this neurotransmitter is primordial in modulating human emotions. This systematic review aims to verify the gene variant's SS (9R/9R) genotype and S (9R) allele frequency fluctuation and its influence on the modulation of pharmacotherapy in MDD. For this purpose, we searched different databases, and after applying the eligibility criteria, six articles were selected. Studies have shown an association between the SS (9R/9R) genotypic and S (9R) allelic presence with the risk of developing MDD, in addition to influencing the decrease in response to antidepressant therapy. However, despite the findings, disagreements were observed between other studies. For this reason, further studies with the () variant in different populations are necessary to understand this polymorphism's role in the onset of this disease.
PubMed: 37626766
DOI: 10.3390/biomedicines11082270 -
Molecular Psychiatry Jul 2023Impairment of insulin action and metabolic dysregulation have traditionally been associated with schizophrenia, although the molecular basis of such association remains... (Meta-Analysis)
Meta-Analysis
Impairment of insulin action and metabolic dysregulation have traditionally been associated with schizophrenia, although the molecular basis of such association remains still elusive. The present meta-analysis aims to assess the impact of insulin action manipulations (i.e., hyperinsulinemia, hypoinsulinemia, systemic or brain insulin resistance) on glutamatergic, dopaminergic, γ-aminobutyric acid (GABA)ergic, and serotonergic pathways in the central nervous system. More than one hundred outcomes, including transcript or protein levels, kinetic parameters, and other components of the neurotransmitter pathways, were collected from cultured cells, animals, or humans, and meta-analyzed by applying a random-effects model and adopting Hedges'g to compare means. Two hundred fifteen studies met the inclusion criteria, of which 180 entered the quantitative synthesis. Significant impairments in key regulators of synaptic plasticity processes were detected as the result of insulin handlings. Specifically, protein levels of N-methyl-D-aspartate receptor (NMDAR) subunits including type 2A (NR2A) (Hedges' g = -0.95, 95%C.I. = -1.50, -0.39; p = 0.001; I = 47.46%) and 2B (NR2B) (Hedges'g = -0.69, 95%C.I. = -1.35, -0.02; p = 0.043; I = 62.09%), and Postsynaptic density protein 95 (PSD-95) (Hedges'g = -0.91, 95%C.I. = -1.51, -0.32; p = 0.003; I = 77.81%) were found reduced in insulin-resistant animal models. Moreover, insulin-resistant animals showed significantly impaired dopamine transporter activity, whereas the dopamine D2 receptor mRNA expression (Hedges'g = 3.259; 95%C.I. = 0.497, 6.020; p = 0.021; I = 90.61%) increased under insulin deficiency conditions. Insulin action modulated glutamate and GABA release, as well as several enzymes involved in GABA and serotonin synthesis. These results suggest that brain neurotransmitter systems are susceptible to insulin signaling abnormalities, resembling the discrete psychotic disorders' neurobiology and possibly contributing to the development of neurobiological hallmarks of treatment-resistant schizophrenia.
Topics: Humans; Animals; Schizophrenia; Insulin; Neurobiology; Disks Large Homolog 4 Protein; Receptors, N-Methyl-D-Aspartate; gamma-Aminobutyric Acid; Neurotransmitter Agents
PubMed: 37085712
DOI: 10.1038/s41380-023-02065-4 -
Movement Disorders Clinical Practice Apr 2023Neuropathological studies, based on small samples, suggest that symptoms of Parkinson's disease (PD) emerge when dopamine/nigrostriatal loss is around 50-80%. Functional... (Review)
Review
BACKGROUND
Neuropathological studies, based on small samples, suggest that symptoms of Parkinson's disease (PD) emerge when dopamine/nigrostriatal loss is around 50-80%. Functional neuroimaging can be applied in larger numbers during life, which allows analysis of the extent of dopamine loss more directly.
OBJECTIVE
To quantify dopamine transporter (DaT) activity by neuroimaging in early PD.
METHODS
Systematic review and novel analysis of DaT imaging studies in early PD.
RESULTS
In our systematic review, in 423 unique cases from 27 studies with disease duration of less than 6 years, mean age 58.0 (SD 11.5) years, and mean disease duration 1.8 (SD 1.2) years, striatal loss was 43.5% (95% CI 41.6, 45.4) contralaterally, and 36.0% (95% CI 33.6, 38.3) ipsilaterally. For unilateral PD, in 436 unique cases, mean age 57.5 (SD 10.2) years, and mean disease duration 1.8 (SD 1.4) years, striatal loss was 40.6% (95% CI 38.8, 42.4) contralaterally, and 31.6% (95% CI 29.4, 33.8) ipsilaterally. In our novel analysis of the Parkinson's Progressive Marker Initiative study, 413 cases had 1436 scans performed. For a disease duration of less than 1 year, age was 61.8 (SD 9.8) years, and striatal loss was 51.2% (95% CI 49.1, 53.3) contralaterally and 39.5% (36.9, 42.1) ipsilaterally, giving an overall striatal loss of 45.3% (43.0, 47.6).
CONCLUSIONS
Loss of striatal DaT activity in early PD is less at 35-45%, rather than the 50-80% striatal dopamine loss estimated to be present at the time of symptom onset, based on backwards extrapolation from autopsy studies.
PubMed: 37070042
DOI: 10.1002/mdc3.13687 -
International Journal of Molecular... Mar 2023Schizophrenia is a severe psychiatric illness affecting almost 25 million people worldwide and is conceptualized as a disorder of synaptic plasticity and brain... (Review)
Review
Canonical and Non-Canonical Antipsychotics' Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia.
Schizophrenia is a severe psychiatric illness affecting almost 25 million people worldwide and is conceptualized as a disorder of synaptic plasticity and brain connectivity. Antipsychotics are the primary pharmacological treatment after more than sixty years after their introduction in therapy. Two findings hold true for all presently available antipsychotics. First, all antipsychotics occupy the dopamine D2 receptor (D2R) as an antagonist or partial agonist, even if with different affinity; second, D2R occupancy is the necessary and probably the sufficient mechanism for antipsychotic effect despite the complexity of antipsychotics' receptor profile. D2R occupancy is followed by coincident or divergent intracellular mechanisms, implying the contribution of cAMP regulation, β-arrestin recruitment, and phospholipase A activation, to quote some of the mechanisms considered canonical. However, in recent years, novel mechanisms related to dopamine function beyond or together with D2R occupancy have emerged. Among these potentially non-canonical mechanisms, the role of Na channels at the dopamine at the presynaptic site, dopamine transporter (DAT) involvement as the main regulator of dopamine concentration at synaptic clefts, and the putative role of antipsychotics as chaperones for intracellular D2R sequestration, should be included. These mechanisms expand the fundamental role of dopamine in schizophrenia therapy and may have relevance to considering putatively new strategies for treatment-resistant schizophrenia (TRS), an extremely severe condition epidemiologically relevant and affecting almost 30% of schizophrenia patients. Here, we performed a critical evaluation of the role of antipsychotics in synaptic plasticity, focusing on their canonical and non-canonical mechanisms of action relevant to the treatment of schizophrenia and their subsequent implication for the pathophysiology and potential therapy of TRS.
Topics: Humans; Antipsychotic Agents; Dopamine; Schizophrenia; Schizophrenia, Treatment-Resistant; beta-Arrestins
PubMed: 36983018
DOI: 10.3390/ijms24065945 -
European Journal of Nuclear Medicine... Jun 2023Dopaminergic scintigraphic imaging is a cornerstone to support the diagnosis in dementia with Lewy bodies. To clarify the current state of knowledge on this imaging... (Review)
Review
INTRODUCTION
Dopaminergic scintigraphic imaging is a cornerstone to support the diagnosis in dementia with Lewy bodies. To clarify the current state of knowledge on this imaging modality and its impact on clinical diagnosis, we performed an updated systematic review of the literature.
METHODS
This systematic review was carried out according to PRISMA guidelines. A comprehensive computer literature search of PubMed/MEDLINE, EMBASE, and Cochrane Library databases for studies published through June 2022 was performed using the following search algorithm: (a) "Lewy body" [TI] OR "Lewy bodies" [TI] and (b) ("DaTscan" OR "ioflupane" OR "123ip" OR "123?ip" OR "123 ip" OR "123i-FP-CIT" OR "FPCIT" OR "FP-CIT" OR "beta?CIT" OR "beta CIT" OR "CIT?SPECT" OR "CIT SPECT" OR "Dat?scan*" OR "dat scan*" OR "dat?spect*" OR "SPECT"). Risk of bias and applicability concerns of the studies were evaluated using the QUADAS-2 tool.
RESULTS
We performed a qualitative analysis of 59 studies. Of the 59 studies, 19 (32%) addressed the diagnostic performance of dopamine transporter imaging, 15 (25%) assessed the identification of dementia with Lewy bodies in the spectrum of Lewy body disease and 18 (31%) investigated the role of functional dopaminergic imaging in distinguishing dementia with Lewy bodies from other dementias. Dopamine transporter loss was correlated with clinical outcomes in 19 studies (32%) and with other functional imaging modalities in 15 studies (25%). Heterogeneous technical aspects were found among the studies through the use of various radioligands, the more prevalent being the [123I]N‑ω‑fluoropropyl‑2β‑carbomethoxy‑3β‑(4‑iodophenyl) nortropane (I-FP-CIT) in 54 studies (91.5%). Image analysis used visual analysis (9 studies, 15%), semi-quantitative analysis (29 studies, 49%), or a combination of both (16 studies, 27%).
CONCLUSION
Our systematic review confirms the major role of dopaminergic scintigraphic imaging in the assessment of dementia with Lewy bodies. Early diagnosis could be facilitated by identifying the prodromes of dementia with Lewy bodies using dopaminergic scintigraphic imaging coupled with emphasis on clinical neuropsychiatric symptoms. Most published studies use a semi-quantitative analytical assessment of tracer uptake, while there are no studies using quantitative analytical methods to measure dopamine transporter loss. The superiority of a purely quantitative approach to assess dopaminergic transmission more accurately needs to be further clarified.
Topics: Humans; Lewy Body Disease; Dopamine Plasma Membrane Transport Proteins; Iodine Radioisotopes; Tomography, Emission-Computed, Single-Photon; Tropanes
PubMed: 36920494
DOI: 10.1007/s00259-023-06154-y -
European Journal of Nuclear Medicine... Jun 2023In routine practice, dopamine transporter (DAT) imaging is frequently used as a diagnostic tool to support the diagnosis of Parkinson's disease or dementia with Lewy...
PURPOSE
In routine practice, dopamine transporter (DAT) imaging is frequently used as a diagnostic tool to support the diagnosis of Parkinson's disease or dementia with Lewy bodies. In 2008, we published a review on which medications and drugs of abuse may influence striatal [I]I-FP-CIT binding and consequently may influence the visual read of an [I]I-FP-CIT SPECT scan. We made recommendations on which drugs should be withdrawn before performing DAT imaging in routine practice. Here, we provide an update of the original work based on published research since 2008.
METHODS
We performed a systematic review of literature without language restriction from January 2008 until November 2022 to evaluate the possible effects of medications and drugs of abuse, including the use of tobacco and alcohol, on striatal DAT binding in humans.
RESULTS
The systematic literature search identified 838 unique publications, of which 44 clinical studies were selected. Using this approach, we found additional evidence to support our original recommendations as well as some new findings on potential effect of other medications on striatal DAT binding. Consequently, we updated the list of medications and drugs of abuse that may influence the visual read of [I]I-FP-CIT SPECT scans in routine clinical practice.
CONCLUSION
We expect that a timely withdrawal of these medications and drugs of abuse before DAT imaging may reduce the incidence of false-positive reporting. Nevertheless, the decision to withdraw any medication must be made by the specialist in charge of the patient's care and considering the pros and cons of doing so.
Topics: Humans; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Imaging; Tomography, Emission-Computed, Single-Photon; Tropanes
PubMed: 36847827
DOI: 10.1007/s00259-023-06171-x