Studies using positron emission tomography to image striatal dopamine function, have demonstrated that individuals with schizophrenia display increases in presynaptic function. Mesolimbic dysfunction ...specifically, has previously been suggested to underlie psychotic symptoms. This has not been directly tested in vivo, and the precise anatomical locus of dopamine dysfunction within the striatum remains unclear. The current article investigates the magnitude of dopaminergic abnormalities in individuals with schizophrenia, and determines how the magnitude of abnormality varies across functional subdivisions of the striatum.
EMBASE, PsychINFO, and MEDLINE were searched from January 1, 1960, to December 1, 2016. Inclusion criteria were molecular imaging studies that had measured presynaptic striatal dopamine functioning. Effects sizes for whole striatum and functional subdivisions were calculated separately. The magnitude of difference between functional subdivisions in patients and controls was meta-analyzed.
Twenty-one eligible studies were identified, including 269 patients and 313 controls. Individuals with schizophrenia (Hedges' g = 0.68, P < .001) demonstrated elevated presynaptic dopamine functioning compared to controls. Seven studies examined functional subdivisions. These demonstrated significant increases in patients compared to controls in associative (g = 0.73, P = .002) and sensorimotor (g = 0.54, P = .005) regions, but not limbic (g = 0.29, P = .09). The magnitude of the difference between associative and limbic subdivisions was significantly greater in patients compared to controls (g = 0.39, P = .003).
In individuals with schizophrenia dopaminergic dysfunction is greater in dorsal compared to limbic subdivisions of the striatum. This is inconsistent with the mesolimbic hypothesis and identifies the dorsal striatum as a target for novel treatment development.
Fifty years on: Serotonin and depression Jauhar, Sameer; Cowen, Philip J; Browning, Michael
Journal of psychopharmacology,
03/2023, Letnik:
37, Številka:
3
Journal Article
Recenzirano
Odprti dostop
It has been over 50 years since the original serotonin hypothesis was proposed by the British Psychiatrist Alec Coppen. Recently, some authors have questioned the validity of the hypothesis. In this ...narrative review, we summarise the evidence for the serotonin hypothesis of depression, focusing on psychopharmacology and molecular imaging, as well as systems-level neuroscience.
FFDOPA PET imaging has shown dopaminergic function indexed as K
differs between antipsychotic treatment responders and non-responders. However, the theragnostic potential of this biomarker to ...identify non-responders has yet to be evaluated. In view of this, we aimed to evaluate this as a theragnostic test using linear and non-linear machine-learning (i.e., Bernoulli, support vector, random forest and Gaussian processes) analyses and to develop and evaluate a simplified approach, standardised uptake value ratio (SUVRc). Both
FFDOPA PET approaches had good test-rest reproducibility across striatal regions (K
ICC: 0.68-0.94, SUVRc ICC: 0.76-0.91). Both our linear and non-linear classification models showed good predictive power to distinguish responders from non-responders (receiver operating curve area under the curve for region-of-interest approach: K
= 0.80, SUVRc = 0.79; for voxel-wise approach using a linear support vector machine: 0.88) and similar sensitivity for identifying treatment non-responders with 100% specificity (K
: ~50%, SUVRc: 40-60%). Although the findings were replicated in two independent datasets, given the total sample size (n = 84) and single setting, they warrant testing in other samples and settings. Preliminary economic analysis of
FFDOPA PET to fast-track treatment-resistant patients with schizophrenia to clozapine indicated a potential healthcare cost saving of ~£3400 (equivalent to $4232 USD) per patient. These findings indicate
FFDOPA PET dopamine imaging has potential as biomarker to guide treatment choice.
Relapse in, and recovery from, schizophrenia has been acknowledged since the disease was first described. In this review the authors summarize the long-term (>100 years) data on relapse and recovery ...in schizophrenia by reviewing the extant older and modern relevant literature. The authors systematically question the utility of pharmacological and nonpharmacological interventions, with an emphasis on first episode nonaffective psychosis. The method used is a narrative review of earlier meta-analytic and systematic reviews.
Antipsychotic medication discontinuation studies suggest a role for prophylactic maintenance treatment in the majority of people with schizophrenia, despite recent debate on this subject. The authors conclude that long-term outcomes, including relapse and recovery rates, have improved in the last 100 years, though prospectively identifying those people who do not require long-term antipsychotic treatment has not yet been possible. Data also suggests that interventions and outcomes during the first 5 years of the disease can influence the long-term schizophrenia trajectory.
IMPORTANCE: The dopamine hypothesis suggests that dopamine abnormalities underlie psychosis, irrespective of diagnosis, implicating dopamine dysregulation in bipolar affective disorder and ...schizophrenia, in line with the research domain criteria approach. However, this hypothesis has not been directly examined in individuals diagnosed with bipolar disorder with psychosis. OBJECTIVES: To test whether dopamine synthesis capacity is elevated in bipolar disorder with psychosis and how this compares with schizophrenia and matched controls and to examine whether dopamine synthesis capacity is associated with psychotic symptom severity, irrespective of diagnostic class. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional case-control positron emission tomographic study was performed in the setting of first-episode psychosis services in an inner-city area (London, England). Sixty individuals participated in the study (22 with bipolar psychosis 18 antipsychotic naive or free, 16 with schizophrenia 14 antipsychotic naive or free, and 22 matched controls) and underwent fluorodihydroxyphenyl-l-alanine (18F-DOPA) positron emission tomography to examine dopamine synthesis capacity. Standardized clinical measures, including the Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning, were administered. The study dates were March 2013 to November 2016. MAIN OUTCOMES AND MEASURES: Dopamine synthesis capacity (Kicer) and clinical measures (Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning). RESULTS: The mean (SD) ages of participants were 23.6 (3.6) years in 22 individuals with bipolar psychosis (13 male), 26.3 (4.4) years in 16 individuals with schizophrenia (14 male), and 24.5 (4.5) years in controls (14 male). There was a significant group difference in striatal dopamine synthesis capacity (Kicer) (F2,57 = 6.80, P = .002). Kicer was significantly elevated in both the bipolar group (mean SD, 13.18 1.08 × 10−3 min−1; P = .002) and the schizophrenia group (mean SD, 12.94 0.79 × 10−3 min−1; P = .04) compared with controls (mean SD, 12.16 0.92 × 10−3 min−1). There was no significant difference in striatal Kicer between the bipolar and schizophrenia groups. Kicer was significantly positively correlated with positive psychotic symptom severity in the combined bipolar and schizophrenia sample experiencing a current psychotic episode, explaining 27% of the variance in symptom severity (n = 32, r = 0.52, P = .003). There was a significant positive association between Kicer and positive psychotic symptom severity in individuals with bipolar disorder experiencing a current psychotic episode (n = 16, r = 0.60, P = .01), which remained significant after adjusting for manic symptom severity. CONCLUSIONS AND RELEVANCE: These findings are consistent with a transdiagnostic role for dopamine dysfunction in the pathoetiology of psychosis and suggest dopamine synthesis capacity as a potential novel drug target for bipolar disorder and schizophrenia.
Background:
Reserpine is an effective antihypertensive drug, but its role in routine practice has declined such that it is rarely used. This is largely based on the assumption that reserpine causes ...depression. This assumption was a foundation for the original monoamine hypothesis of depression. However, there remains conflicting evidence as to whether reserpine causes depression, and no systematic review of available evidence.
Aims:
We systematically reviewed evidence on effects of reserpine on depressive and related symptoms (e.g. anxiety, suicidal ideation).
Method:
Electronic searches of MEDLINE, Embase and PsycINFO were conducted to identify studies up to 14 February 2021. Studies of any methodological design involving reserpine-treated and reserpine-untreated conditions, in any adult human population, were included and a narrative synthesis of findings was undertaken. Risk of bias (RoB) was examined using ROBINS-I.
Results:
Of the 35 studies meeting inclusion criteria, 9 were randomised controlled trials. Eleven studies reported some depressogenic effects, 13 reported no effect and 11 reported putative antidepressant effects. Studies identifying depressive effects were more likely to examine people without psychiatric disorders at baseline, while studies identifying a potential antidepressant effect tended to treat fewer participants for shorter durations, at higher doses. Around one-third of studies conducted in people with psychiatric disorders showed beneficial effects on depression symptoms. 30/35 studies were at high RoB.
Conclusions:
Associations between reserpine and depression are inconsistent and limited by a lack of high-quality evidence. Due to reserpine’s apparently complex effects, we urge nuance rather than simplicity surrounding the monoamine hypothesis of depression.
The randomised controlled trial of antipsychotic reduction and discontinuation addresses essential questions with regard to continued use of antipsychotics in schizophrenia, pertaining to social ...functioning and continued antipsychotic use. However, significant methodological issues stated in the trial protocol have the potential to confound interpretation of any findings. These include use of a non-blinded outcome measure, treatment as usual comparator and possible sample size issues.
PDF
