•We show links between serotonin and neuroplasticity in depression and antidepressant treatment.•Serotonin reuptake inhibitors mediate development-like neuroplasticity.•Neuroplasticity is measureable ...in vivo in humans with magnetic resonance imaging.•Translational MRI and histology studies should be promoted in depression models.
Serotonin modulates neuroplasticity, especially during early life, and dysfunctions in both systems likewise contribute to pathophysiology of depression. Recent findings demonstrate that serotonin reuptake inhibitors trigger reactivation of juvenile-like neuroplasticity. How these findings translate to clinical antidepressant treatment in major depressive disorder remains unclear. With this review, we link preclinical with clinical work on serotonin and neuroplasticity to bring two pathophysiologic models in clinical depression closer together. Dysfunctional developmental plasticity impacts on later-life cognitive and emotional functions, changes of synaptic serotonin levels and receptor levels are coupled with altered synaptic plasticity and neurogenesis. Structural magnetic resonance imaging in patients reveals disease-state-specific reductions of gray matter, a marker of neuroplasticity, and reversibility upon selective serotonin reuptake inhibitor treatment. Translational evidence from magnetic resonance imaging in animals support that reduced densities and sizes of neurons and reduced hippocampal volumes in depressive patients could be attributable to changes of serotonergic neuroplasticity. Since ketamine, physical exercise or learning enhance neuroplasticity, combinatory paradigms with selective serotonin reuptake inhibitors could enhance clinical treatment of depression.
Treatment outcomes for major depressive disorder (MDD) need to be improved. Presently, no clinically relevant tools have been established for stratifying subgroups or predicting outcomes. This ...literature review sought to investigate factors closely linked to outcome and summarize existing and novel strategies for improvement. The results show that early recognition and treatment are crucial, as duration of untreated depression correlates with worse outcomes. Early improvement is associated with response and remission, while comorbidities prolong course of illness. Potential biomarkers have been explored, including hippocampal volumes, neuronal activity of the anterior cingulate cortex, and levels of brain-derived neurotrophic factor (BDNF) and central and peripheral inflammatory markers (e.g., translocator protein (TSPO), interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor alpha (TNFα)). However, their integration into routine clinical care has not yet been fully elucidated, and more research is needed in this regard. Genetic findings suggest that testing for CYP450 isoenzyme activity may improve treatment outcomes. Strategies such as managing risk factors, improving clinical trial methodology, and designing structured step-by-step treatments are also beneficial. Finally, drawing on existing guidelines, we outline a sequential treatment optimization paradigm for selecting first-, second-, and third-line treatments for acute and chronically ill patients. Well-established treatments such as electroconvulsive therapy (ECT) are clinically relevant for treatment-resistant populations, and novel transcranial stimulation methods such as theta-burst stimulation (TBS) and magnetic seizure therapy (MST) have shown promising results. Novel rapid-acting antidepressants, such as ketamine, may also constitute a paradigm shift in treatment optimization for MDD.
Pleasure and motivation are important factors for goal-directed behavior and well-being in both animals and humans. Intact hedonic capacity requires an undisturbed interplay between a number of ...different brain regions and transmitter systems. Concordantly, dysfunction of networks encoding for reward have been shown in depression and other psychiatric disorders. The development of technological possibilities to investigate connectivity on a functional level in humans and to directly influence networks in animals using optogenetics among other techniques has provided new important insights in this field of research.In this review, we aim to provide an overview on the neurobiological substrates of anhedonia on a network level. For this purpose, definition of anhedonia and the involved reward components are described first, then current data on reward networks in healthy individuals and in depressed patients are summarized, and the roles of different neurotransmitter systems involved in reward processing are specified. Based on this information, the impact of different therapeutic approaches on reward processing is described with a particular focus on deep brain stimulation (DBS) as a possibility for a direct modulation of human brain structures in vivo.Overall, results of current studies emphasize the importance of anhedonia in psychiatric disorders and the relevance of targeting this phenotype for a successful psychiatric treatment. However, more data incorporating these results for the refinement of methodological approaches are needed to be able to develop individually tailored therapeutic concepts based on both clinical and neurobiological profiles of patients.
The serotonin system plays an important role in the neural processing of anxiety. The involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT1A) subtype, in dysfunctional ...forms of anxiety has been supported by findings from a wide range of preclinical research and clinical trials, including treatment studies, genetic research, and neuroimaging data. The following article summarizes preclinical results with a focus on 5-HT1A receptor knockout and transgenic mice as genetic models of anxiety. Behavioral, autonomic, and endocrinological changes in these mice are reported. This article also presents genetic polymorphisms in humans associated with increased anxiety scores and pharmacological data focused on 5-HT1A receptor agonists and antagonists. Furthermore, molecular neuroimaging results are presented. Recent positron emission tomography (PET) studies have reported reduced 5-HT1A receptor binding in patients with panic disorder and social anxiety disorder, but not in posttraumatic stress disorder. In healthy subjects, increased anxiety scores might be associated with lower 5-HT1A receptor binding. This overview of preclinical and clinical data provides strong evidence for the key role of the 5-HT1A receptor in the serotonergic dysregulation of anxiety disorders.
Background:
Many patients with obsessive-compulsive disorder do not respond adequately to serotonin reuptake inhibitors. Augmentation with antipsychotic drugs can be beneficial in this regard. ...However, since new relevant randomized controlled trials evaluating new antipsychotics were conducted, a recalculation of the effect sizes appears necessary.
Methods:
We meta-analyzed all double-blind, randomized, placebo-controlled trials comparing augmentation of serotonin reuptake inhibitors with antipsychotics to placebo supplementation in treatment-resistant obsessive-compulsive disorder. The primary outcome was mean change in the Yale-Brown Obsessive–Compulsive Scale total score. Secondary outcomes were obsessions, compulsions, response rates, and attrition rates. The data collection process was conducted independently by 2 authors. Hedges’s g and risks ratios were calculated as effect sizes. In preplanned meta-regressions, subgroup analyses, and sensitivity analyses, we examined the robustness of the results and explored reasons for potential heterogeneity.
Results:
Altogether, 14 double-blind, randomized, placebo-controlled trials (n=491) investigating quetiapine (N=4, n=142), risperidone (N=4, n=132), aripiprazole (N=2, n=79), olanzapine (N=2, n=70), paliperidone (N=1, n=34), and haloperidol (N=1, n=34) were incorporated. Augmentation with antipsychotics was significantly more efficacious than placebo in Yale-Brown Obsessive–Compulsive Scale total reduction (N=14, n=478; Hedges’s g=-0.64, 95% CI: -0.87 to -0.41; P=<.01). Aripiprazole (Hedges’s g=-1.35), haloperidol (Hedges’s g=-0.82), and risperidone (Hedges’s g=-0.59) significantly outperformed placebo. Antipsychotics were superior to placebo in treating obsessions, compulsions, and achieving response. There was no between-group difference concerning all-cause discontinuation. The nonsignificant meta-regressions suggest no influence of the antipsychotic dose or baseline symptom severity on the meta-analytic results.
Conclusions:
According to our findings, antipsychotic augmentation of serotonin reuptake inhibitors can be regarded as an evidence-based measure in treatment-resistant obsessive-compulsive disorder.
Second generation antipsychotics (SGAs) are effective options in the treatment of schizophrenia and mood disorders, each with characteristic efficacy and safety features. In order to optimize the ...balance between efficacy and side effects, it is of upmost importance to match compound specificity against patient clinical profile. As the number of SGAs increased, this review can assist physicians in the prescription of three novel SGAs already on the market, namely lurasidone, brexpiprazole, cariprazine, and lumateperone, which is in the approval phase for schizophrenia treatment at the FDA.
Besides schizophrenia, EMA and/or FDA approved lurasidone for bipolar depression, brexpiprazole as augmentation in major depressive disorder and cariprazine for the acute treatment of manic or mixed episodes associated with bipolar I disorder. These new antipsychotics were developed with the aim of improving efficacy on negative and depressive symptoms and reducing metabolic and cardiovascular side effects compared to prior SGAs, while keeping the risk of extrapyramidal symptoms low. They succeeded quite well in containing these side effects, despite weight gain during acute treatment remains a possible concern for brexpiprazole, while cariprazine and lurasidone show higher risk of akathisia compared to placebo and other SGAs such as olanzapine. The available studies support the expected benefits on negative symptoms, cognitive dysfunction and depressive symptoms, while the overall effect on acute psychotic symptoms may be similar to other SGAs such as quetiapine, aripiprazole and ziprasidone.
The discussed new antipsychotics represent useful therapeutic options but their efficacy and side effect profiles should be considered to personalize prescription.
Intranasal esketamine for treatment-resistant depression has been introduced and approved by the FDA and EMA in 2019 and 2020, respectively. Since then, the administration practices were found ...different among countries. Major depression has a high impact on many humans lives worldwide and more than a third of treated people are not responding after several treatment attempts. Additional administration with esketamine closed this gap for more than the half of these non-responders. Guidelines for the treatment of major depression recommend starting with add-on esketamine after 2-4 serious attempts of treatment with standard antidepressants (SSRI/SNRI) irrespective of augmentation with others, e.g., second generation antipsychotics or lithium. Thus, intranasal esketamine became an important role in the evidence-based treatment of major depression. The authors review and critically evaluated published articles focusing on preparation, management and observation of intranasal esketamine treatment. There exists a clear recommendation for administrating intranasal esketamine in a medical environment, not limited to a clinical setting for selecting the dose, monitoring the improvements and managing adverse events. The administration of intranasal esketamine is considered as safe during the application itself and long-lasting or severe adverse events during long-term treatment are very rare. Since this is a new approach for treatment application psychiatrists face new different but not difficult treatment procedures compared to prescribing only a medication.
Social anxiety disorder patients suffer from excessive anxious responses in social interaction leading to avoidance behavior and social impairment. Although the amygdala has a central role in ...perception and processing of threatening cues, little is known about the involved networks and corresponding dysfunctions in social anxiety. Therefore, this study aims to investigate the functional connectivity network of the amygdala in patients with social anxiety disorder and to identify regions that might influence amygdalar reactivity via modulatory pathways.
Ten patients with anxiety disorders (social and/or panic) and 27 healthy controls underwent a facial emotion processing task as well as 6-min functional MRI at resting state. Individual voxel-wise functional connectivity maps were calculated using the amygdala as seed region. Group comparisons were done by random-effects analysis in SPM.
Patients exhibited an amygdala hyperactivation during the emotional task and decreased functional coupling of the left amygdala with the medial orbitofrontal cortex and the posterior cingulate cortex/precuneus. The strength of this functional connectivity showed a negative association with the severity of state anxiety. In addition, an exploratory analysis revealed further reduced functional connectivity and a marked functional separation between the medial orbitofrontal and anterior cingulate cortices in the patient group.
Our results suggest alterations within the amygdalar functional connectivity network in social anxiety disorder. Combined with the amygdalar hyperactivation our findings corroborate the proposed dysfunction of the fronto-amygdalar inhibition in anxiety disorders and indicate a modulatory influence of the anterior and posterior cingulate cortices on threat perception and processing.
►Resting state functional connectivity of amygdala in social anxiety disorder. ►Reduced amygdala connectivity with orbitofrontal and posterior cingulate cortices. ►Decreased coupling between orbitofrontal and anterior cingulate cortices.
Although post-COVID-19 syndrome (PCS) with cognitive impairment is increasingly encountered in primary care, evidence-based recommendations for its appropriate management are lacking.
A systematic ...literature search evaluating the diagnosis and treatment of cognitive impairment associated with PCS was conducted. Practical recommendations for the management of PCS-associated cognitive impairment in primary care are summarized, based on an evaluation of pharmacological plausibility and clinical applications.
Currently, the pathology of cognitive impairment associated with PCS remains unclear with no high-quality data to support targeted interventions. Existing treatment approaches are directed towards symptom relief where counseling on the chronicity of the disease and regular reassessments at 4- to 8-week intervals is considered reasonable. Patients should be informed and encouraged to adopt a healthy lifestyle that centers around balanced nutrition and appropriate physical activities. They may also benefit from the intake of vitamins, micronutrients, and probiotics. The administration of
extract could offer a safe and potentially beneficial treatment option. Other non-pharmacological measures include physiotherapy, digitally supported cognitive training, and, if indicated, ergotherapy or speech therapy. In most patients, symptoms improve within 8 weeks. If serious, ambiguous, or when new symptoms occur, specialized diagnostic measures such as comprehensive neurocognitive testing or neuroimaging should be initiated. Very few patients would require inpatient rehabilitation.
PCS with cognitive impairment is a debilitating condition that could affect daily functioning and reduce work productivity. Management in primary care should adopt a multidisciplinary approach, centering around physical, cognitive, and pharmacological therapies.
Abstract
Background:
The current paper introduces the actual International College of Neuro-Psychopharmacology clinical guidelines for the treatment of bipolar disorder.
Concept and structure of the ...guidelines:
The current clinical guidelines are based on evidence-based data, but they also intend to be clinically useful, while a rigid algorithm was developed on the basis of firm evidence alone. Monotherapy was prioritized over combination therapy. There are separate recommendations for each of the major phases of bipolar disorder expressed as a 5-step algorithm.
Discussion:
The current International College of Neuro-Psychopharmacology clinical guidelines for the treatment of bipolar disorder are the most up-to-date guidance and are as evidence based as possible. They also include recommendations concerning the use of psychotherapeutic interventions, again on the basis of available evidence. This adherence of the workgroup to the evidence in a clinically oriented way helped to clarify the role of specific antidepressants and traditional agents like lithium, valproate, or carbamazepine. The additional focus on specific clinical characteristics, including predominant polarity, mixed features, and rapid cycling, is also a novel approach. Many issues need further studies, data are sparse and insufficient, and many questions remain unanswered. The most important and still unmet need is to merge all the guidelines that concern different phases of the illness into a single one and in this way consider BD as a single unified disorder, which is the real world fact. However, to date the research data do not permit such a unified approach.
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