Patients' attitudes toward conventional and herbal treatments for depression and anxiety: A cross-sectional Israeli survey.

BACKGROUND: As many patients view conventional antidepressants and anxiolytics negatively, it is not surprising that the willingness to apply these treatments is far from ideal, thus posing a critical barrier in promoting an effective and durable treatment. AIM: The present study aimed to explore patients' attitudes toward conventional and herbal treatments for depression and anxiety, while considering cultural and demographic factors, to further elucidate the antecedes that putatively determine the treatment's outcome. METHODS: During June 2017, a cross-sectional survey was conducted using stratified sampling from a large-scale Israeli volunteer online panel. The final sample included 591 Jewish Israeli adults that reported they were suffering from depression or anxiety. RESULTS: A heterogeneous range of attitudes toward treatment was found: for example, a large group of patients did not utilize prescription medications (39%), a professional consultation (12.9%), or any form of treatment (17.4%). Interestingly, these patients were significantly more likely to support naturally-derived treatments and were less concerned with scientific proof. Further, adverse effects were demonstrated as a prominent factor in the choice of treatment. A higher incidence of adverse effects was associated with an increased willingness to consider an alternative herbal treatment. Noteworthy attitudes were found in orthodox-Jewish individuals, who showed similar consultation rates, but utilized more psychological, rather than pharmacological treatments. CONCLUSIONS: It is proposed that patients' perspectives and cultural backgrounds are needed to be taken into consideration during the clinical assessment and choice of treatment. The findings imply that a particular emphasis should be placed on patients that discard conventional pharmacological options and on distinct cultural aspects. Several recommendations for revising the current policy are advocated to promote more culturally-informed and patient-oriented care.

The Brainstem-Informed Autism Framework: Early Life Neurobehavioral Markers.

Autism spectrum disorders (ASD) have long-term implications on functioning at multiple levels. In this perspective, we offer a brainstem-informed autism framework (BIAF) that traces the protracted neurobehavioral manifestations of ASD to early life brainstem dysfunctions. Early life brainstem-mediated markers involving functions of autonomic/arousal regulation, sleep-wake homeostasis, and sensorimotor integration are delineated. Their possible contributions to the early identification of susceptible infants are discussed. We suggest that the BIAF expands our multidimensional understanding of ASD by focusing on the early involvement of brainstem systems. Importantly, we propose an integrated BIAF screener that brings about the prospect of a sensitive and reliable early life diagnostic scheme for weighing the risk for ASD. The BIAF screener could provide clinicians substantial gains in the future and may carve customized interventions long before the current DSM ASD phenotype is manifested using dyadic co-regulation of brainstem-informed autism markers.

Moderation of the transgenerational transference of antenatal stress-induced anxiety.

Maternal stress has debilitating implications for both mother and child, including increased risk for anxiety. The current COVID-19 pandemic escalates these phenomena, thus, urging the need to further explore and validate feasible therapeutic options. Unlike the protracted nature of clinical studies, animal models could offer swift evidence. Prominent candidates for treatment are selective serotonin reuptake inhibitors (SSRIs) to the mother, that putatively accommodate maternal functioning, and, thereby, also protect the child. However, SSRIs might have deleterious effects. It is important to assess whether SSRIs and other pharmacotherapies can moderate the transference of anxiety by soothing maternal anxiety and to examine the extent of offspring's exposure to the drugs via lactation. To our knowledge, the possibility that antenatal stress exacerbates lactation-driven exposure to SSRIs has not been tested yet. Thirty ICR-outbred female mice were exposed to stress during gestation and subsequently administered with either the SSRI, escitalopram, or the novel herbal candidate, shan-zha, during lactation. Upon weaning, both dams' and pups' anxiety-like behavior and serum escitalopram levels were assessed. The major findings of the current study show that both agents moderated the antenatal stress-induced transgenerational transference of anxiety by ameliorating dams' anxiety. Interestingly though, pups' exposure to escitalopram via lactation was exacerbated by antenatal stress. The latter finding provides a significant insight into the mechanism of lactation-driven exposure to xenobiotics and calls for a further consideration vis-à-vis the administration of other drugs during breastfeeding.

Preterm Birth and the Development of Visual Attention During the First 2 Years of Life: A Systematic Review and Meta-analysis.

Importance: Preterm birth is associated with an increased risk for long-lasting attention deficits. Early-life markers of attention abnormalities have not been established to date but could provide insights into the pathogenesis of attention abnormalities and could help identify susceptible individuals. Objective: To examine whether preterm birth is associated with visual attention impairments in early life, and if so, in which attention functions and at which developmental period during the first 2 years of life. Data Sources: PubMed and PsycINFO were searched on November 17, 2019, to identify studies involving visual attention outcomes in infants born preterm vs full term. Study Selection: Peer-reviewed studies from the past 50 years met the eligibility criteria if they directly assessed visual attention outcomes until the age of 2 years in generally healthy infants born preterm or full term. The selection process was conducted by 2 independent reviewers. Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline was followed. Random-effects models were used to determine standardized mean differences. The risk of bias was assessed both within and between studies. Main Outcomes and Measures: Five nascent indices of visual attention were analyzed, including very basic functions-namely, the abilities to follow and fixate on visual targets-and more complex functions, such as visual processing (ie, habituation), recognition memory (ie, novelty preference), and the ability to effortfully focus attention for learning. Results: A total of 53 studies were included, with 69 effect sizes and assessing a total of 3998 infants (2047 born preterm and 1951 born full term; of the 3376 for whom sex was reported, 1693 [50.1%] were girls). Preterm birth was associated with impairments in various attention indices, including visual-following in infancy (Cohen d, -0.77; 95% CI, -1.23 to -0.31), latency to fixate (Cohen d, -0.18; 95% CI, -0.33 to -0.02), novelty preference (Cohen d, -0.20; 95% CI, -0.32 to -0.08), and focused attention (Cohen d, -0.28; 95% CI, -0.45 to -0.11). In the neonatal period, preterm birth was associated with superior visual-following (Cohen d, 0.22; 95% CI, 0.03 to 0.40), possibly owing to the additional extrauterine exposure to sensory stimulation. However, this early association waned rapidly in infancy (Cohen d, -0.77; 95% CI, -1.23 to -0.31). Conclusions and Relevance: The findings suggest that preterm birth is associated with impingements to visual attention development in early life, as manifested in basic and then complex forms of attention. Advancements in neonatal care may underlie improvements found in the current era and accentuate several early protective factors.

Cerebral MAO Activity Is Not Altered by a Novel Herbal Antidepressant Treatment.

Inhibition of monoamine oxidase (MAO)-A/B can ameliorate depressive- and anxiety-related symptoms via increase of monoamine extracellular levels. However, such inhibition can also instigate hypertensive response following exposure to dietary tyramine (i.e., "the cheese effect"). Novel herbal treatment (NHT) is an herbal formula that has been demonstrated to reduce depressive- and anxiety-like symptoms in pre-clinical studies. The aim of the current study was to examine whether the therapeutic potential of NHT is underlain by inhibition of MAO-A/B and whether NHT poses a risk for tyramine hyper-potentiation. Unpredictable chronic mild stress (UCMS)-exposed mice and naïve mice were treated for 3 weeks with NHT (30 mg/kg; i.p.), the selective serotonin reuptake inhibitor (SSRI) escitalopram (15 mg/kg; i.p.), or saline. Subsequently, MAO-A/B activities in the hypothalamus, striatum, and prefrontal cortex (PFC) were assessed. Exposure to UCMS led to significant increases in both MAO-A and MAO-B activities in the hypothalamus (p < 0.001) and in the PFC (p < 0.01 for MAO-A; p < 0.001 for MAO-B). Neither NHT nor escitalopram had any notable effects. Treatment with NHT was supported as safe in terms of risk for inducing a hypertensive response. The antidepressant- and anxiolytic-like effects of NHT are mediated via pathways other than MAO-A/B inhibition.

The Unpredictable Chronic Mild Stress Protocol for Inducing Anhedonia in Mice.

Depression is a highly prevalent and debilitating condition, only partially addressed by current pharmacotherapies. The lack of response to treatment by many patients prompts the need to develop new therapeutic alternatives and to better understand the etiology of the disorder. Pre-clinical models with translational merits are rudimentary for this task. Here we present a protocol for the unpredictable chronic mild stress (UCMS) method in mice. In this protocol, adolescent mice are chronically exposed to interchanging unpredictable mild stressors. Resembling the pathogenesis of depression in humans, stress exposure during the sensitive period of mice adolescence instigates a depressive-like phenotype evident in adulthood. UCMS can be used for screenings of antidepressants on the variety of depressive-like behaviors and neuromolecular indices. Among the more prominent tests to assess depressive-like behavior in rodents is the sucrose preference test (SPT), which reflects anhedonia (core symptom of depression). The SPT will also be presented in this protocol. The ability of UCMS to induce anhedonia, instigate long-term behavioral deficits and enable reversal of these deficits via chronic (but not acute) treatment with antidepressants strengthens the protocol's validity compared to other animal protocols for inducing depressive-like behaviors.

GABAA Receptor Density Is Not Altered by a Novel Herbal Anxiolytic Treatment.

Anxiety disorders are highly prevalent and considered a major public health concern worldwide. Current anxiolytics are of limited efficacy and associated with various side effects. Our novel herbal treatment (NHT), composed of four constituents, was shown to reduce anxiety-like behavior while precluding a common side effect caused by current anxiolytics, i.e., sexual dysfunction. Nevertheless, NHT's mechanism of action is yet to be determined. There is evidence that some medicinal herbs interact with the GABAergic system. Therefore, we aimed to examine whether NHT's anxiolytic-like effect is exerted by alterations in GABAA receptor density in the hippocampus, prefrontal cortex, and hypothalamus. The effects of 3-weeks treatment with NHT on anxiety-like behavior and locomotion were assessed using the elevated plus maze (EPM) and the open field test (OFT), respectively. Regional GABAA receptor levels were analyzed using [3H] RO15-1788 high-affinity binding assays. In stressed mice, NHT reduced anxiety-like behavior similarly to the benzodiazepine, clonazepam, while locomotion remained intact. Lack of changes or minor changes in regional GABAA receptor density in the brain were induced by NHT or clonazepam. In naive mice, performance in the EPM, locomotion and GABAA receptor densities were not altered by treatment with NHT or clonazepam. These findings support NHT as an efficacious and safe anxiolytic, although the GABAergic involvement remains to be further elucidated.

Cannabinoids prevent depressive-like symptoms and alterations in BDNF expression in a rat model of PTSD.

Posttraumatic stress disorder (PTSD) is a debilitating condition highly comorbid with depression. The endocannabinoid (eCB) system and brain-derived neurotrophic factor (BDNF) are suggestively involved in both disorders. We examined whether cannabinoids can prevent the long-term depressive-like symptoms induced by exposure to the shock and situational reminders (SRs) model of PTSD. The CB1/2 receptor agonist WIN55,212-2 (0.5 mg/kg; i.p.), the fatty acid hydrolase (FAAH) inhibitor URB597 (0.3 mg/kg, i.p.) or vehicle were administered 2 h after severe shock. Cannabinoids prevented the shock/SRs-induced alterations in social recognition memory, locomotion, passive coping, anxiety-like behavior, anhedonia, fear retrieval, fear extinction and startle response as well as the decrease in BDNF levels in the hippocampus and prefrontal cortex (PFC). Furthermore, significant correlations were found between depressive-like behaviors and BDNF levels in the brain. The findings suggest that cannabinoids may prevent both depressive- and PTSD-like symptoms following exposure to severe stress and that alterations in BDNF levels in the brains' fear circuit are involved in these effects.

Escitalopram and NHT normalized stress-induced anhedonia and molecular neuroadaptations in a mouse model of depression.

Anhedonia is defined as a diminished ability to obtain pleasure from otherwise positive stimuli. Anxiety and mood disorders have been previously associated with dysregulation of the reward system, with anhedonia as a core element of major depressive disorder (MDD). The aim of the present study was to investigate whether stress-induced anhedonia could be prevented by treatments with escitalopram or novel herbal treatment (NHT) in an animal model of depression. Unpredictable chronic mild stress (UCMS) was administered for 4 weeks on ICR outbred mice. Following stress exposure, animals were randomly assigned to pharmacological treatment groups (i.e., saline, escitalopram or NHT). Treatments were delivered for 3 weeks. Hedonic tone was examined via ethanol and sucrose preferences. Biological indices pertinent to MDD and anhedonia were assessed: namely, hippocampal brain-derived neurotrophic factor (BDNF) and striatal dopamine receptor D2 (Drd2) mRNA expression levels. The results indicate that the UCMS-induced reductions in ethanol or sucrose preferences were normalized by escitalopram or NHT. This implies a resemblance between sucrose and ethanol in their hedonic-eliciting property. On a neurobiological aspect, UCMS-induced reduction in hippocampal BDNF levels was normalized by escitalopram or NHT, while UCMS-induced reduction in striatal Drd2 mRNA levels was normalized solely by NHT. The results accentuate the association of stress and anhedonia, and pinpoint a distinct effect for NHT on striatal Drd2 expression.