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The European Journal of Neuroscience Mar 2024Dopamine, a catecholamine neurotransmitter, has historically been associated with the encoding of reward, whereas its role in aversion has received less attention. Here,...
Dopamine, a catecholamine neurotransmitter, has historically been associated with the encoding of reward, whereas its role in aversion has received less attention. Here, we systematically gathered the vast evidence of the role of dopamine in the simplest forms of aversive learning: classical fear conditioning and extinction. In the past, crude methods were used to augment or inhibit dopamine to study its relationship with fear conditioning and extinction. More advanced techniques such as conditional genetic, chemogenic and optogenetic approaches now provide causal evidence for dopamine's role in these learning processes. Dopamine neurons encode conditioned stimuli during fear conditioning and extinction and convey the signal via activation of D receptor sites particularly in the amygdala, prefrontal cortex and striatum. The coordinated activation of dopamine receptors allows for the continuous formation, consolidation, retrieval and updating of fear and extinction memory in a dynamic and reciprocal manner. Based on the reviewed literature, we conclude that dopamine is crucial for the encoding of classical fear conditioning and extinction and contributes in a way that is comparable to its role in encoding reward.
Topics: Dopamine; Extinction, Psychological; Conditioning, Classical; Fear; Prefrontal Cortex; Avoidance Learning
PubMed: 37848184
DOI: 10.1111/ejn.16157 -
Journal of Clinical Psychopharmacology Dec 2014Brain imaging data of antipsychotics have mainly been derived from oral antipsychotic drugs, which hampers our understanding of the requirement of dose/dosing frequency... (Review)
Review
Brain imaging data of antipsychotics have mainly been derived from oral antipsychotic drugs, which hampers our understanding of the requirement of dose/dosing frequency of long-acting injectable (LAI) antipsychotics for the maintenance treatment of schizophrenia. A systematic literature search was performed to identify positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies that assessed dopamine D2 receptor occupancy levels with LAI antipsychotic drugs in humans, using PubMed, EMBASE, and PsycINFO (last search, February 2013). Twenty studies (15 PET and 5 SPECT studies) were identified. The most investigated drug in these PET and SPECT studies was haloperidol decanoate (44 subjects; 11 studies), followed by risperidone LAI (24 subjects; 3 studies), olanzapine pamoate (14 subject; 1 study), and fluphenazine decanoate (12 subjects; 3 studies). The data have demonstrated high and continuous D2 receptor blockade with LAIs; the effects of LAI first-generation antipsychotics on the central nervous system may persist for several months. The prospective and cross-sectional studies showed that continuous dopamine D2 receptor blockade above 65% (ie, the lower end of the established therapeutic window for the acute phase treatment) was not always necessary for maintenance treatment for at least some of the patients. In conclusion, because of the limited brain imaging data on LAI antipsychotics, we still do not know the best way to dose them. Still, the currently available brain imaging data raises a possibility that the dosing interval of LAI antipsychotics may be extended beyond the currently indicated range in some patients.
Topics: Antipsychotic Agents; Brain; Cross-Sectional Studies; Delayed-Action Preparations; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Injections, Intramuscular; Positron-Emission Tomography; Prospective Studies; Tomography, Emission-Computed, Single-Photon
PubMed: 24781442
DOI: 10.1097/JCP.0000000000000065 -
Schizophrenia Bulletin Nov 2016Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of... (Meta-Analysis)
Meta-Analysis Review
Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (≥7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naïve youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2-20, n = 81-2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5-Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05-.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges' g's = 0.30-0.80, ORs = 1.47-1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1-2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets.
Topics: Antipsychotic Agents; Humans; Pharmacogenetics; Psychotic Disorders; Weight Gain
PubMed: 27217270
DOI: 10.1093/schbul/sbw058 -
Pharmacology & Therapeutics Aug 2022Almost fifty years after its first introduction into clinical care, clozapine remains the only evidence-based pharmacological option for treatment-resistant... (Review)
Review
Clozapine's multiple cellular mechanisms: What do we know after more than fifty years? A systematic review and critical assessment of translational mechanisms relevant for innovative strategies in treatment-resistant schizophrenia.
Almost fifty years after its first introduction into clinical care, clozapine remains the only evidence-based pharmacological option for treatment-resistant schizophrenia (TRS), which affects approximately 30% of patients with schizophrenia. Despite the long-time experience with clozapine, the specific mechanism of action (MOA) responsible for its superior efficacy among antipsychotics is still elusive, both at the receptor and intracellular signaling level. This systematic review is aimed at critically assessing the role and specific relevance of clozapine's multimodal actions, dissecting those mechanisms that under a translational perspective could shed light on molecular targets worth to be considered for further innovative antipsychotic development. In vivo and in vitro preclinical findings, supported by innovative techniques and methods, together with pharmacogenomic and in vivo functional studies, point to multiple and possibly overlapping MOAs. To better explore this crucial issue, the specific affinity for 5-HTR, D1R, α, and muscarinic receptors, the relatively low occupancy at dopamine D2R, the interaction with receptor dimers, as well as the potential confounder effects resulting in biased ligand action, and lastly, the role of the moiety responsible for lipophilic and alkaline features of clozapine are highlighted. Finally, the role of transcription and protein changes at the synaptic level, and the possibility that clozapine can directly impact synaptic architecture are addressed. Although clozapine's exact MOAs that contribute to its unique efficacy and some of its severe adverse effects have not been fully understood, relevant information can be gleaned from recent mechanistic understandings that may help design much needed additional therapeutic strategies for TRS.
Topics: Antipsychotic Agents; Clozapine; Humans; Receptors, Dopamine D2; Schizophrenia; Schizophrenia, Treatment-Resistant
PubMed: 35764175
DOI: 10.1016/j.pharmthera.2022.108236 -
Journal of Psychiatric Research May 2017While positron emission tomography (PET) studies have provided invaluable data on antipsychotic effects, selection bias remains a serious concern. A systematic review of... (Review)
Review
While positron emission tomography (PET) studies have provided invaluable data on antipsychotic effects, selection bias remains a serious concern. A systematic review of PET studies that measured dopamine D receptor blockade with antipsychotics was conducted to examine their inclusion/exclusion criteria, using PubMed, EMBASE, and ClinicalTrials.gov (last search, September 2016). PET studies were included if they measured D receptor occupancy in patients with schizophrenia and included introduction of antipsychotic treatment or antipsychotic regimen change in a systematic manner. Twenty-six studies were identified. Age limit was included in 13 studies; one study solely included geriatric patients while others targeted younger adults. Eleven, 6, and 3 studies specifically targeted clinically stable patients, patients with severe psychopathology, and antipsychotic-free patients, respectively. Nineteen and 18 studies excluded patients with physical comorbidity and substance abuse, respectively. As a result, the mean age of subjects ranged from 23 to 42 years when one study that targeted geriatric patients was excluded. Mean Positive and Negative Syndrome Scale total scores ranged from 54 to 95. No comparison active-drug or placebo arm was employed in 24 studies. Blind assessment of symptomatology was performed in 5 studies. In general, subjects participating in clinical PET studies were relatively young, presented with mild symptomatology, and were free from substance abuse or physical comorbidities. These characteristics need to be taken into account when clinical PET data are interpreted. On the other hand, it should also be noted that this study was only qualitative and conservative interpretation is necessary for possibility of subjective bias.
Topics: Adult; Clinical Trials as Topic; Databases, Factual; Female; Humans; Male; Positron-Emission Tomography; Schizophrenia; Young Adult
PubMed: 28088727
DOI: 10.1016/j.jpsychires.2016.12.023 -
Translational Psychiatry Jan 2017Disrupted-in-Schizophrenia 1 (DISC1) is a gene known as a risk factor for mental illnesses possibly associated with dopamine impairments. DISC1 is a scaffold protein... (Review)
Review
Disrupted-in-Schizophrenia 1 (DISC1) is a gene known as a risk factor for mental illnesses possibly associated with dopamine impairments. DISC1 is a scaffold protein interacting with proteins involved in the dopamine system. Here we summarise the impact of DISC1 disruption on the dopamine system in animal models, considering its effects on presynaptic dopaminergic function (tyrosine hydroxylase levels, dopamine transporter levels, dopamine levels at baseline and after amphetamine administration) and postsynaptic dopaminergic function (dopamine D1 and D2 receptor levels, dopamine receptor-binding potential and locomotor activity after amphetamine administration). Our findings show that many but not all DISC1 models display (1) increased locomotion after amphetamine administration, (2) increased dopamine levels after amphetamine administration in the nucleus accumbens, and (3) inconsistent basal dopamine levels, dopamine receptor levels and binding potentials. There is also limited evidence for decreased tyrosine hydroxylase levels in the frontal cortex and increased dopamine transporter levels in the striatum but not nucleus accumbens, but these conclusions warrant further replication. The main dopaminergic findings are seen across different DISC1 models, providing convergent evidence that DISC1 has a role in regulating dopaminergic function. These results implicate dopaminergic dysregulation as a mechanism underlying the increased rate of schizophrenia seen in DISC1 variant carriers, and provide insights into how DISC1, and potentially DISC1-interacting proteins such as AKT and GSK-3, could be used as novel therapeutic targets for schizophrenia.
Topics: Amphetamine; Animals; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Locomotion; Mice; Nerve Tissue Proteins; Nucleus Accumbens; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2; Tyrosine 3-Monooxygenase
PubMed: 28140405
DOI: 10.1038/tp.2016.282 -
BMJ Neurology Open 2024The aim of this manuscript is to review the evidence and compare the efficacy and safety of catechol-O-methyltransferase inhibitors (COMT-Is), dopamine receptor agonists...
BACKGROUND
The aim of this manuscript is to review the evidence and compare the efficacy and safety of catechol-O-methyltransferase inhibitors (COMT-Is), dopamine receptor agonists (DRAs) and monoamine-oxidase B inhibitors (MAOB-Is) as adjunctive treatment to levodopa in patients with Parkinson's disease (PD) experiencing motor complications.
METHODS
In this systematic review and network meta-analysis, literature searches were performed in MEDLINE and Embase to identify eligible randomised controlled trials (RCTs) with a minimal follow-up of at least 4 weeks published in English between 1980 and 2021. RCTs were included if either a COMT-I, DRA or MAOB-I was evaluated as an adjunctive therapy to levodopa in patients with PD experiencing motor complications and dyskinesia. The main outcomes included daily off-medication time, motor and non-motor examination scales, and adverse events including dyskinesia.
RESULTS
74 RCTs reporting on 18 693 patients were included. All three studied drug classes decreased daily off-medication time compared with placebo (COMT-Is mean -0.8 hours (95% CI -1.0 to -0.6), DRAs -1.1 hours (95% CI -1.4 to -0.8), MAOB-Is -0.9 hours (95% CI -1.2 to -0.6)). Safety analysis showed an increased risk of dyskinesia for all three drug classes (COMT-Is OR 3.3 (95% CI 2.7 to 4.0), DRAs 3.0 (95% CI 2.5 to 3.5), MAOB-Is 1.6 (95% CI 1.2 to 2.2)). According to surface under the cumulative ranking curve scores, pramipexole IR was associated with the most favourable benefit-risk profile.
CONCLUSIONS
COMT-Is, DRAs and MAOB-Is effectively reduce motor complications and increase incidence of dyskinesia. In the network meta-analysis, adjunctive use of DRAs appeared most effective.
PubMed: 38352047
DOI: 10.1136/bmjno-2023-000573 -
Headache Jan 2016We sought to conduct a qualitative systematic review to evaluate the safety and efficacy of available treatments for pediatric patients with migraine or benign primary... (Review)
Review
OBJECTIVE
We sought to conduct a qualitative systematic review to evaluate the safety and efficacy of available treatments for pediatric patients with migraine or benign primary headache in the emergency department, in an effort to inform future practice.
METHODS
Scopus, Medline, and PubMed databases were searched for randomized controlled trials retrospective reviews, review articles, and case studies discussing migraine or benign primary headache management that were conducted in the emergency room or outpatient acute care setting in pediatric patients (less than 18-years old). Meeting abstracts and cited references within articles were also evaluated. Multiple variables were recorded, including type of treatment, study design, dosing, primary outcome, and side effects. Therapeutic gain was calculated in studies with a placebo arm. Treatments were subjectively assessed based on methodology and number of trials for a particular therapy.
RESULTS
Thirty-one studies were included in the final analysis. Of these, 17 were randomized controlled trials, 9 were retrospective reviews, and 5 were prospective chart review studies. One pertained to IV fluids, 2 to nonspecific analgesic use, 5 to dopamine receptor antagonists, 2 to valproic acid, 1 to propofol, 1 to magnesium, 1 to bupivicaine, 13 to triptan medications, and 3 to dihydroergotamine (DHE). Treatments considered effective for acute migraine or benign primary headache in the analgesic category include ibuprofen, and to a lesser degree acetaminophen. Ketorolac was not compared to other NSAIDs, but was found to be less effective than prochlorperazine. Of the phenothiazines, prochlorperazine was considered most effective. Of the triptan medications, almotriptan, rizatriptan, zolmitriptan nasal spray, sumatriptan nasal spray, and combination sumatriptan/naproxen are effective agents for acute treatment. Treatments considered probably effective included IV fluids, chlorpromazine, valproate sodium, injectable sumatriptan, and IV DHE. Treatments with oral zolmitriptan showed inconsistent results, while treatments considered ineffective included isolated oral sumatriptan and oral DHE. There is insufficient evidence to comment on propofol, magnesium, and bupivicaine efficacy.
CONCLUSIONS
Of the available evidence, ibuprofen, prochlorperazine, and certain triptan medications are the most effective and safe agents for acute management of migraine and other benign headache disorders in the pediatric population. Additional studies in this population are needed, and should take into consideration variables such as dosing, co-administered medications, treatment duration, and length of treatment effect.
Topics: Child; Child, Preschool; Emergency Service, Hospital; Humans; Migraine Disorders; Pediatrics; Treatment Outcome
PubMed: 26790849
DOI: 10.1111/head.12746 -
International Journal of Clinical... Sep 2015To describe the efficacy, tolerability and safety of brexpiprazole for the treatment of schizophrenia and as adjunct for major depressive disorder (MDD). (Review)
Review
Brexpiprazole for schizophrenia and as adjunct for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antipsychotic - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed?
OBJECTIVE
To describe the efficacy, tolerability and safety of brexpiprazole for the treatment of schizophrenia and as adjunct for major depressive disorder (MDD).
DATA SOURCES
The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms 'brexpiprazole' OR 'OPC-34712', and by also querying the EMBASE (Elsevier) commercial database for clinical poster abstracts, and by asking the manufacturer for copies of posters presented at congresses. Product labelling provided additional information.
STUDY SELECTION
All available clinical reports of studies were identified.
DATA EXTRACTION
Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information.
DATA SYNTHESIS
Brexpiprazole is a new dopamine D2 receptor partial agonist that received approval for the treatment of schizophrenia and for adjunctive use for the treatment of MDD based on a clinical trial development programme that included two pivotal Phase III trials of brexpiprazole monotherapy in acute schizophrenia, and two pivotal Phase III trials of adjunctive brexpiprazole in acute MDD in patients who demonstrated inadequate response to standard antidepressant therapy. In addition, results from a 52-week relapse prevention/maintenance randomised placebo-controlled withdrawal study in patients with schizophrenia are available. In these trials, brexpiprazole was administered once daily and titrated to target doses. The recommended dose for the treatment of schizophrenia is 2-4 mg/day and that for MDD, 2 mg/day. Pooling together all the available data for the recommended target dose of brexpiprazole for acute schizophrenia from the above studies, the percentage of responders is 45.5% vs. 31.0% for placebo, yielding a NNT of 7 (95% CI 5-12). In the relapse prevention/maintenance trial, significantly fewer patients relapsed in the brexpiprazole group compared with placebo (13.5% vs. 38.5%), resulting in a NNT of 4 (95% CI 3-8). When the results for brexpiprazole 1, 2 and 3 mg from the two Phase III MDD trials are pooled together, 23.2% of the patients receiving brexpiprazole were responders, vs. 14.5% for placebo, yielding a NNT of 12 (95% CI 8-26). Brexpiprazole was well tolerated - for schizophrenia, discontinuation rates because of an adverse event (AE) were overall lower for patients receiving brexpiprazole vs. placebo, and for MDD a total of 3% of brexpiprazole-treated patients and 1% of placebo-treated patients discontinued because of AEs, resulting in a NNH of 53 (95% CI 30-235). Although the most commonly encountered AE noted in product labelling was akathisia (5.5% in the acute schizophrenia trials and 8.6% in the MDD trials), differences from placebo were small, generating a non-significant NNH of 112 for patients with schizophrenia and a modest NNH of 15 (95% CI 11-23) for patients with MDD. Short-term weight gain appears modest; however, more outliers with an increase of ≥ 7% of body weight were evident in open-label 52-week safety studies. Effects on glucose and lipids were small. Minimal effects on prolactin were observed, and no clinically relevant effects on the ECG QT interval were evident.
CONCLUSIONS
Clinical trials of brexpiprazole support its efficacy at the recommended target dose of 2-4 mg/day for the treatment of schizophrenia, and at the recommended target dose of 2 mg/day as adjunct to antidepressant medication for the treatment of MDD. Head-to-head comparisons with other available agents among patients with schizophrenia and MDD in the 'real world' are needed.
Topics: Antidepressive Agents; Antipsychotic Agents; Chemotherapy, Adjuvant; Clinical Trials as Topic; Depressive Disorder, Major; Dopamine Agonists; Humans; Quinolones; Schizophrenia; Thiophenes
PubMed: 26250067
DOI: 10.1111/ijcp.12714 -
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