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Purpose: Postpartum mood disorders affect many women following childbirth. Prescribing medication for depression and anxiety is one strategy for the effective treatment of postpartum mood disorders. Left untreated, mothers experiencing these disorders and their infants face increased risks of adverse health outcomes. Little is known about how diagnosis and treatment of postpartum mood disorders changed during COVID-19., Methods: We used a retrospective pooled cross-sectional design in a sample of privately-insured postpartum women in U.S. claims data from January 1, 2016 to December 31, 2020. We measured changes in diagnoses of anxiety and depression and changes in prescription fills and days supplied of classes of medications used to treat these conditions (antidepressants, benzodiazepines, and z-drugs). We used ordinary least squares (OLS) regression for each outcome variable during the pre-pandemic period and forecast expected outcomes the observation period. Forecasted and actual values of the outcomes were then compared., Results: Following the onset of the COVID-19 pandemic in March 2020, diagnoses of depression and anxiety were not significantly higher among privately insured postpartum women in the United States. The proportion of privately-insured postpartum women filling a benzodiazepine prescription increased by 15.2%., Conclusions: We find diagnosis of postpartum mood disorders did not increase after the onset of the COVID-19 pandemic, however, fills of benzodiazepines increased among privately-insured postpartum women. Given prior evidence of increased depressive and anxiety symptoms among postpartum women during COVID-19, this suggests increased barriers to appropriate diagnoses and treatment for depression during this period., Competing Interests: Declarations. Competing interest: The authors have no competing interests to declare., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Collaborative care management (CoCM) is an evidenced based approach to psychiatric treatment in primary care, yet literature examining factors associated with program adherence is lacking. This study analyzed predictors of adherence to a CoCM model of psychopharmacological treatment of depression and anxiety in primary care by conducting a retrospective cohort analysis on Veterans referred to a large VA Medical Center's CoCM program over an 18-month period. Baseline characteristics, symptomatic assessments, and covariates of interest were collected. For the primary outcome, the association between covariates and programmatic completion were analyzed. Secondary analyses assessed improvements in psychiatric symptoms. A total of 757 Veterans with depressive or anxiety disorders were included, and 256 completed the CoCM program. Baseline covariates associated with differences in completion rates included the following: age, contact with psychology prior to referral, baseline PHQ-9, baseline GAD-7, and a number of comorbid psychiatric/substance abuse covariates. After controlling for baseline differences, age remained a significant positive predictor of completion (OR 1.019, 95% CI 1.008‒1.030) and cannabis use a significant negative predictor (OR 0.507, 95% CI 0.275‒0.934). Both early improvement in PHQ-9 (OR 1.864, 95% CI 1.210‒2.872) and GAD-7 (OR 1.762, 95% CI 1.154‒2.691) scores were positive predictors. Secondary analyses showed that programmatic completion was associated with greater reductions in psychiatric symptoms. Results identified a number of modifiable parameters associated with differences in completion rates and greater symptomatic reduction for those who complete the program. Additional studies should be conducted examining interventions to optimize CoCM programs by supporting positive predictors while minimizing negative predictors., Competing Interests: Declarations. Conflict of Interest: The authors declare no competing interests., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Child and adolescent anxiety disorders (ADs) contribute to impairment in social functioning and peer relationships, exacerbating anxiety and related difficulties. The extent to which the AD treatment with the strongest evidence-base, cognitive-behavioral therapy (CBT), improves social functioning and peer relationships is unclear. In this article, we report results of the first systematic narrative review of this topic. Randomized clinical trials of CBT for child and/or adolescent ADs were included if they used at least one measure of social functioning or peer relationships as a treatment outcome. Sixteen studies met our inclusion criteria. From each study, we extracted the sample characteristics, treatment arms, social and/or peer outcome measures, and statistical findings. Results show that social functioning and/or peer relationships improved over time in the majority of studies, highlighting an important aspect of treatment efficacy beyond anxiety reduction. There were also several treatment-specific effects, but considerable variability across studies' samples, methods, and findings, makes it difficult to draw firm conclusions about which specific treatments improve specific outcomes. We recommend next steps for research to reconcile these findings, including improved operationalization and standardization of social and peer outcomes, and research on treatment specificity and mechanisms., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Depression and anxiety disorders carry a tremendous worldwide burden and emerge as a significant cause of disability among western societies. Both disorders are known to disproportionally affect women, as they are twice more likely to be diagnosed and moreover, they are also prone to suffer from female-specific mood disorders. Importantly, the prevalence of these affective disorders has notably risen after the COVID pandemic, especially in women. In this chapter, we describe factors that are possibly contributing to the expression of such sex differences in depression and anxiety. For this, we overview the effect of transcriptomic and genetic factors, the immune system, neuroendocrine aspects, and cognition. Furthermore, we also provide evidence of sex differences in antidepressant response and their causes. Finally, we emphasize the importance to consider sex as a biological variable in preclinical and clinical research, which may facilitate the discovery and development of new and more efficacious antidepressant and anxiolytic pharmacotherapies for both women and men., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Based on mounting clinical and translational evidence demonstrating the impact of exogenously administered inflammatory stimuli on the brain and behavior, increased endogenous inflammation has received attention as one pathophysiologic process contributing to psychiatric illnesses and particularly depression. Increased endogenous inflammation is observed in a significant proportion of depressed patients and has been associated with reduced responsiveness to standard antidepressant therapies. This chapter presents recent evidence that inflammation affects neurotransmitters and neurocircuits to contribute to specific depressive symptoms including anhedonia, motor slowing, and anxiety, which may preferentially improve after anti-cytokine therapies in patients with evidence of increased inflammation. Existing and novel pharmacological strategies that target inflammation or its downstream effects on the brain and behavior will be discussed in the context of a need for intelligent trial design in order to meaningfully translate these concepts and develop more precise therapies for depressed patients with increased inflammation., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: In 2011, direct healthcare professional communication (DHPC) letters on citalopram and escitalopram were sent out to address the risk of QTc prolongation in the ECG. Healthcare professionals were informed about a reduction of the maximum recommended daily dose. Furthermore, a contraindication for QTc-prolonging co-medication was given. Previous studies noted that these instructions were implemented incompletely., Aim: For the first time, this study analyzed how the DHPC affected the prescription of citalopram and escitalopram in patients with anxiety disorders., Methods: Drug utilization data from the project "Arzneimittelsicherheit in der Psychiatrie e. V." (AMSP) was used to examine whether the proportion of patients treated with a higher-than-recommended daily dose ("high dose") and the proportion of patients with QTc-prolonging co-medication would decrease post-DHPC (combined category of citalopram/escitalopram)., Results: Drug utilization data of n = 364 patients pre- and n = 262 patients post-DHPC were compared. The proportion of patients with high dose declined from 10.7% to 5.4% (p = 0.019). The proportion of patients with QTc-prolonging co-medication did not change significantly from pre- (54.7%) to post-DHPC (51.5%, p = 0.437)., Discussion: In accordance with previous studies, the proportion of high-dose patients decreased after DHPC publication while the proportion of patients with QTc-prolonging co-medication remained widely unchanged. The specific recommendation on daily dosage seems to have been better implemented than the broadly formulated contraindication of QTc-prolonging co-medication. Hence, DHPCs should be written precisely and give advice for specific clinical situations., (© 2022. Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature.)

Background: In France, despite the known risks, the use of benzodiazepines and related (BZD) is excessive, particularly in older populations. Over the age of 70, 1 person in 2 uses BZD on a long-term basis (more than 3 years), whereas it is recommended not to exceed 12 weeks. To compensate for the numerous undesirable effects and to maintain a positive benefit-risk balance, these treatments must be very effective and improve significantly the quality of life., Aims: This study aims to determine whether the efficacy of BZD outweighs their adverse effects in older population., Methods: In a population of 109 patients with cognitive impairment and hospitalized in Saint-Quentin (France), we recorded the use of BZD and medical background. Neuropsychological and geriatric assessments allowed cognitive and thymic evaluation., Results: In our cohort of 109 patients, 50% of the subjects were BZD + and 78% were women. Patients in the BZD + group were no longer anxious but had poorer cognitive and executive performance than controls., Discussion: Long-term treatment of anxiety in patients aged 75 and over with BZD appears to be effective. The deleterious impact of BZD on cognition has been demonstrated., Conclusions: These results tend to consider non-medicinal therapies as serious alternatives to BZD for treating anxiety in the older population., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain, acts at the ionotropic GABA A and GABA C receptors, and the metabotropic GABA B receptor. This chapter summarizes the studies that have investigated the role of the GABA B receptor in stress-related psychiatric disorders including anxiety and mood disorders. Overall, clinical and preclinical evidences strongly suggest that the GABA B receptor is a therapeutic candidate for depression and anxiety disorders. However, the clinical development of GABA B receptor-based drugs to treat these disorders has been hampered by their potential side-effects, particularly those of agonists. Nevertheless, the discovery of novel GABA B receptor allosteric modulators, and increasing understanding of the influence of specific intracellular GABA B receptor-associated proteins on GABA B receptor activity, may now pave the way towards GABA B receptor therapeutics in the treatment of mood and anxiety disorders., (© 2020. Springer Nature Switzerland AG.)

Access to the Internet has upended long-standing myths and misconceptions about autism as autistic individuals are enabled through technology increasingly to influence the dialog around neurodiversity, the experience of being autistic, and the effectiveness of mental health interventions for autistic adults. Autistic self-advocates are speaking up in support of including neurodivergent adults as a population that might benefit from the burgeoning psychedelic medicine field, in an absence of many other mental health treatment options that have been researched and shown to be effective for them. Autism is a genetically-determined neurocognitive variant with considerable heterogeneity across the broad autistic phenotype spectrum. Therefore, enthusiasm for investigating psychedelics to cure or alter the course of autism is most likely ill-informed and misdirected; psychiatric and psychopharmacological interventions do not alter the genome. However, autism frequently co-occurs with clinical conditions such as anxiety, depression, obsessive-compulsive disorder, and trauma that have been investigated as indications for clinical trials with classic and atypical psychedelics. The purpose of this chapter will be to inform researchers and clinicians on the history of clinical research with classic psychedelics with autistic minors, recent and current clinical trials of atypical psychedelics with autistic adults, and considerations for providing psychedelic-assisted psychotherapies that are compatible with autism., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

This research examined whether pediatric inpatients without an anxiety/mood disorder are more likely to receive opioids in response to pain compared to patients diagnosed with a mental health condition. Research questions were tested using cross-sectional inpatient electronic medical record data. Propensity score matching was used to match patients with a disorder with patients without the disorder (anxiety analyses: N = 2892; mood analyses: N = 1042). Although patients with anxiety and mood disorders experienced greater pain, physicians were less likely to order opioids for these patients. Analyses also disclosed an interaction of anxiety with pain-the pain-opioid relation was stronger for patients without an anxiety disorder than for patients with an anxiety diagnosis. Instead, physicians were more likely to place non-opioid analgesic orders to manage the pain of patients with anxiety disorders. Findings imply that pain management decisions might be influenced by patient's mental health., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Co-morbid anxiety disorders, including generalized anxiety disorder (GAD), are highly prevalent among individuals with Williams syndrome (WS). However, reports of the pharmacologic treatment of only a limited number of previous anxiety disorders in WS have appeared in the literature. Here, we review the case histories of three adolescents/young adults with WS and the treatment course of co-morbid GAD with buspirone. Treatment with buspirone was well-tolerated and resulted in sustained response in all three cases. Common medical disorders in WS are highlighted with regards to safe and appropriate pharmacologic treatment of GAD. Buspirone's generally benign side effect profile is a major benefit of its use for treating GAD in individuals with WS.

This study examined the relationship between caregivers' and youths' treatment expectations and characteristics of exposure tasks (quantity, mastery, compliance) in cognitive-behavioral therapy (CBT) for childhood anxiety. Additionally, compliance with exposure tasks was tested as a mediator of the relationship between treatment expectations and symptom improvement. Data were from youth (N = 279; 7-17 years old) enrolled in the Child/Adolescent Anxiety Multimodal Study (CAMS) and randomized to cognitive-behavioral therapy (CBT) or the combination of CBT and sertraline for the treatment of separation anxiety disorder, generalized anxiety disorder, and social phobia. Caregivers and youth independently reported treatment expectations prior to randomization, anxiety was assessed pre- and post-treatment by independent evaluators blind to treatment condition, and exposure characteristics were recorded by the cognitive-behavioral therapists following each session. For both caregivers and youths, more positive expectations that anxiety would improve with treatment were associated with greater compliance with exposure tasks, and compliance mediated the relationship between treatment expectations and change in anxiety symptoms following treatment. Additionally, more positive parent treatment expectations were related to a greater number and percentage of sessions with exposure. More positive youth treatment expectations were associated with greater mastery during sessions focused on exposure. Findings underscore the importance of addressing parents' and youths' treatment expectations at the outset of therapy to facilitate engagement in exposure and maximize therapeutic gains.

This study investigated the effects of vitamin D supplementation on Generalized Anxiety Disorder (GAD) clinical symptoms and neurochemical biomarkers including serotonin, neopterin and kynurenine. Thirty male and female patients diagnosed with GAD and had vitamin D deficiency were recruited from the psychiatric clinic at King Abdulaziz University Hospital and divided into two groups; one group of patients (n = 15) received standard of care (SOC) plus 50,000 IU vitamin D (once/week) for 3 months, while the other group (n = 15) received SOC alone. Biochemical parameters including serum vitamin D, serotonin, neopterin and kynurenine were measured for all patients enrolled in the trial. In addition, the Generalized Anxiety Disorder 7-item (GAD-7) scale was used to measure the severity of GAD symptoms in both vitamin D treated- and untreated-patients. Significant improvements in GAD scores were observed in the vitamin D-treated group compared to the group that did not receive vitamin D. In addition, serum serotonin concentrations were significantly increased while serum neopterin were significantly decreased in vitamin D-treated vs. untreated patients. In contrast, no significant differences were found in serum kynurenine concentrations at the end of the study period between the two groups. No changes either in GAD-7 scores or in any of the biochemical measurements were observed in the group that received only SOC after 3 months. Vitamin D supplementation was effective in ameliorating the severity of GAD symptoms by increasing serotonin concentrations and decreasing the levels of the inflammatory biomarker neopterin in GAD patients.

Background A 12-month pilot was implemented in two general practices in remote and rural Scotland, with patients referred by general practitioners to specialist mental health pharmacist independent prescribers. Objective The objective was to evaluate the pilot service from the perspectives of the patients and the care team. Methods The pharmacists routinely recorded patient-specific data of all clinical issues and their actions at the time of each consultation. Further datasets comprised baseline and follow-up Patient Health Questionnaire (PHQ-9) and/or Generalised Anxiety Disorder (GAD-7) rating scales, a patient survey and interviews with members of the care team. Results Of the 75 patients, two-thirds (n = 47, 62.7%) were referred with a diagnosis of mixed depression and anxiety. There were 324 consultations (median 3, IQR 2-5, range 1-14) and 181 prescribing actions. At pilot completion, 34 patients (45.3%) had PHQ-9 and/or GAD-7 scores reduced by 50%. Patient questionnaires and staff interviews generated positive responses. Conclusion This pilot has provided evidence that specialist mental health pharmacist independent prescribers delivered quality care to patients with diagnoses of moderate to severe depression and/or anxiety. Whilst accepting study limitations, there is potential to translate the pilot model of care to sustained services throughout general practice.

Endometriosis is a gynecological condition affecting 10% of women in reproductive age. High rates of depression and anxiety are observed in these patients. The mechanisms underlying endometriosis-induced behavioral alterations are still elusive. Animal models provide a useful tool to study the temporal sequence and biological pathways involved in this disease and comorbid states. Here, we sought to characterize time-related behavioral alterations in rats submitted to endometriosis model (EM) induced by peritoneal auto-transplantation of uterine tissues weekly for three weeks. Corticosterone stress reactivity, oxidative stress markers - reduced glutathione (GSH), lipid peroxidation, activity of superoxide dismutase (SOD) and myeloperoxidase (MPO) - and brain-derived-neurotrophic factor (BDNF) levels in the hippocampus were also evaluated. We observed a progressive increase in anxiety-like behavior from 14th to 21st days post-EM. Despair-like behavior was observed from the 14th day post-EM on, while anhedonia and apathetic-like behaviors accompanied by increased corticosterone stress response were detected on 21 days post-EM. Increased pain sensitivity was observed from the 7th day post-EM and was accompanied by increased endometrioma weight. The pro-oxidative alterations, decreased GSH and increased SOD activity were observed on 21 days post-EM, except for lipid peroxidation that was altered from the 14th day. Decreased BDNF also occurred on the 21st day. Therefore, this study demonstrates that EM is related to several features of clinical depression and proposes the contribution of hippocampal oxidative state and neurotrophic support for the emergence of these changes. Our results support the use of this model as a useful tool to test new strategies for endometriosis-related neuropsychiatric symptoms.

Many pregnant and postpartum women worldwide suffer from high anxiety and/or depression, which can have detrimental effects on maternal and infant well-being. The first-line pharmacotherapies for prepartum and postpartum affective disorders continue to be the selective serotonin reuptake inhibitors (SSRIs), despite the lack of large well-controlled studies demonstrating their efficacy in reproducing women and the potential for fetal/neonatal exposure to the drugs. Prepartum or postpartum use of SSRIs or other drugs that modulate the brain's serotonin system is also troubling because very little is known about the typical, let alone the atypical, changes that occur in the female central serotonin system across reproduction. We do know from a handful of studies of women and female laboratory rodents that numerous aspects of the central serotonin system are naturally dynamic across reproduction and are also affected by pregnancy stress (a major predisposing factor for maternal psychopathology). Thus, it should not be assumed that the maternal central serotonin system being targeted by SSRIs is identical to non-parous females or males. More information about the normative and stress-derailed changes in the maternal central serotonin system is essential for understanding how serotonin is involved in the etiology of, and the best use of SSRIs for potentially treating, affective disorders in the pregnant and postpartum populations.

Benzodiazepines (BDZs) are widespread psychotropic compounds, often prescribed as first-line symptomatic option by general practitioners in patients with different psychiatric disorders. Sometimes, however, they contribute to delay the administration of the first appropriate psychopharmacological treatment, thus leading to a longer duration of untreated illness in patients with depressive and anxiety disorders. The well-established pros of BDZs use in clinical practice include efficacy, rapidity of action, versatility, and safety. Among the cons, BDZs can provoke cognitive side-effects, asthenia, and misuse/abuse. Although their overall safety has been traditionally viewed as one of their greatest strengths, BDZs massive ingestion for suicidal purposes may pose, in some cases, serious life-threatening conditions, as described in the present case report. Hence, particular attention needs to be paid in prescribing these compounds to special populations, such as elderly patients. Among these, their prescription should be limited to the short-term and particularly monitored in case of risk factors, as they may be unsafe in case of overdose.

The aim of this study was to evaluate the effects of atorvastatin and simvastatin on behavioral manifestations that followed hyperhomocysteinemia induced by special dietary protocols enriched in methionine and deficient in B vitamins (B6, B9, B12) by means of alterations in anxiety levels in rats. Simultaneously, we investigated the alterations of oxidative stress markers in rat hippocampus induced by applied dietary protocols. Furthermore, considering the well-known antioxidant properties of statins, we attempted to assess their impact on major markers of oxidative stress and their possible beneficial role on anxiety-like behavior effect in rats. The 4-week-old male Wistar albino rats were divided (eight per group) according to basic dietary protocols: standard chow, methionine-enriched, and methionine-enriched vitamins B (B6, B9, B12) deficient. Each dietary protocol (30 days) included groups with atorvastatin (3 mg/kg/day i.p.) and simvastatin (5 mg/kg/day i.p.). The behavioral testing was performed in the open field and elevated plus maze tests. Parameters of oxidative stress (index of lipid peroxidation, superoxide dismutase, catalase activity, glutathione) were determined in hippocampal tissue samples following decapitation after anesthesia. Methionine-load dietary protocols induced increased oxidative stress in rat hippocampus, which was accompanied by anxiogenic behavioral manifestations. The methionine-enriched diet with restricted vitamins B intake induced more pronounced anxiogenic effect, as well as increased oxidative stress compared to the methionine-load diet with normal vitamins B content. Simultaneous administration of statins showed beneficial effects by means of both decreased parameters of oxidative stress and attenuation of anxiety. The results obtained with simvastatin were more convincible compared to atorvastatin.

Rodent marble-burying behavior in the marble-burying test (MBT) is employed as a model or measure to study anxiety- and compulsive-like behaviors or anxiolytic and anticompulsive drug action. However, the test responds variably to a range of pharmacological interventions, and little consensus exists regarding specific methodologies for its execution. Regardless, the test is widely applied to investigate the effects of pharmacological, genetic, and behavioral manipulations on purported behaviors related to the said neuropsychiatric constructs. Therefore, in the present review we attempt to expound the collective translational significance of the MBT. We do this by (1) reviewing burying behavior as a natural behavioral phenotype, (2) highlighting key aspects of anxiety and obsessive-compulsive disorder from a translational perspective, (3) reviewing the history and proof of concept of the MBT, (4) critically appraising potential methodological confounds in execution of the MBT, and (5) dissecting responses of the MBT to various pharmacological interventions. We conclude by underlining that the collective translational value of the MBT will be strengthened by contextually valid experimental designs and objective reporting of data.

While there is mounting evidence of abnormal reactivity of several brain regions in social anxiety disorder, and disrupted functional connectivity between these regions at rest, relatively little is known regarding resting regional neural activity in these structures, or how such activity is affected by pharmacotherapy. Using 2-deoxy-2-(F-18)fluoro-D-glucose positron emission tomography, we compared resting regional brain metabolism between SAD and healthy control groups; and in SAD participants before and after moclobemide therapy. Voxel-based analyses were confined to a predefined search volume. A second, exploratory whole-brain analysis was conducted using a more liberal statistical threshold. Fifteen SAD participants and fifteen matched controls were included in the group comparison. A subgroup of SAD participants (n = 11) was included in the therapy effect comparison. No significant clusters were identified in the primary analysis. In the exploratory analysis, the SAD group exhibited increased metabolism in left fusiform gyrus and right temporal pole. After therapy, SAD participants exhibited reductions in regional metabolism in a medial dorsal prefrontal region and increases in right caudate, right insula and left postcentral gyrus. This study adds to the limited existing work on resting regional brain activity in SAD and the effects of therapy. The negative results of our primary analysis suggest that resting regional activity differences in the disorder, and moclobemide effects on regional metabolism, if present, are small. While the outcomes of our secondary analysis should be interpreted with caution, they may contribute to formulating future hypotheses or in pooled analyses.

In this chapter, we introduce a new area of social pharmacology that encompasses the study of the role of neuromodulators in modulating a wide range of social behaviors and brain function, with the interplay of genetic and epigenetic factors. There are increasing evidences for the role of the neuropeptide oxytocin in modulating a wide range of social behaviors, in reducing anxiety, and in impacting the social brain network. Oxytocin also promotes social functions in patients with neuropsychiatric disorders, such as autism and reduces anxiety and fear in anxiety disorders. In this chapter, we will emphasize the importance of integrating basic research and clinical human research in determining optimal strategies for drug discoveries for social dysfunctions and anxiety disorders. We will highlight the significance of adopting a precision medicine approach to optimize targeted treatments with oxytocin in neuropsychiatry. Oxytocin effects on social behavior and brain function can vary from one individual to another based on external factors, such as heterogeneity in autism phenotype, childhood experiences, personality, attachment style, and oxytocin receptor polymorphisms. Hence, targeted therapies for subgroups of patients can help alleviating some of the core symptoms and lead to a better future for these patients and their families.

This chapter reviews what is known about the therapeutic uses of the serotonergic or classic hallucinogens, i.e., psychoactive drugs such as LSD and psilocybin that exert their effects primarily through agonist activity at serotonin 2A (5HT2A) receptors. Following a review of the history of human use and scientific study of these drugs, the data from clinical research are summarized, including extensive work on the use of classic hallucinogens in the treatment of alcoholism and other addictions, studies of the use of LSD and psilocybin to relieve distress concerning death, particularly in patients with advanced or terminal cancer, and more limited data concerning the use of classic hallucinogens to treat mood and anxiety disorders. A survey of possible mechanisms of clinically relevant effects is provided. The well-established safety of classic hallucinogens is reviewed. To provide a clinical perspective, case summaries are provided of two individuals who received treatment in recent controlled trials of psilocybin: one being treated for alcoholism, the other suffering from anxiety and depression related to fear of death due to a cancer diagnosis. Although promising early phase research conducted from the 1950s through the early 1970s was discontinued before firm conclusions could be reached concerning the efficacy of any of the classic hallucinogens for any clinical condition, the research that was conducted in that era strongly suggests that classic hallucinogens have clinically relevant effects, particularly in the case of LSD treatment of alcoholism. In the past decade, clinical trials have resumed investigating the effects of classic hallucinogens in the treatment of existential distress in the face of cancer, and in the treatment of addictions including alcoholism and nicotine addiction. The studies that have been completed to date are not sufficient to establish efficacy, but the outcomes have been very encouraging, and larger trials, up to and including phase 3, are now underway or being planned. Although research has elucidated many of the acute neurobiological and psychological effects of classic hallucinogens on humans, animals, and in vitro systems, the mechanisms of clinically relevant persisting effects remain poorly understood.

Drug discrimination is a powerful tool for evaluating the stimulus effects of psychoactive drugs and for linking these effects to pharmacological mechanisms. This chapter reviews the primary findings from drug discrimination studies of antidepressant and anxiolytic drugs, including novel pharmacological mechanisms. The stimulus properties revealed from these animal studies largely correspond to the receptor affinities of antidepressant and anxiolytic drugs, indicating that subjective effects may correspond to either therapeutic or side effects of these medications. We discuss drug discrimination findings concerning adjunctive medications and novel pharmacologic strategies in antidepressant and anxiolytic research. Future directions for drug discrimination work include an urgent need to explore the subjective effects of medications in animal models, to better understand shifts in stimulus sensitivity during prolonged treatments, and to further characterize stimulus effects in female subjects. We conclude that drug discrimination is an informative preclinical procedure that reveals the interoceptive effects of pharmacological mechanisms as they relate to behaviors that are not captured in other preclinical models.

Pediatric anxiety disorders are common, disabling, and chronic conditions. Efforts over the past two decades have focused on developing and testing effective treatments. Short-term efficacy of both Cognitive Behavioral Therapy (CBT) and selective serotonin reuptake inhibitors has been established. Data are emerging on the long-term (i.e., 2 years or longer) effectiveness of these treatments, but this literature has yet to be adequately synthesized. This study presents a systematic and critical qualitative review of published long-term follow-up (LTFU) studies of youth treated for an anxiety disorder. A comprehensive search of several databases identified 21 published reports (representing 15 LTFU cohorts of treated youth) meeting specified inclusion criteria. LTFU assessments occurred a mean of 5.85 years after initial treatment (range 2-19 years). Diagnostic rates at LTFU and predictors (e.g., demographic, baseline child clinical variables, treatment type) of outcomes at LTFU were also examined. A discussion of the limitations of this literature is provided to qualify interpretations of findings and to inform future studies. Findings can aid clinicians and families in making treatment decisions and setting reasonable expectations for the long-term prognosis after treatment for anxiety.

Cyclic nucleotide PDEs are a super-family of enzymes responsible for regulating intracellular levels of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Through their catalysis, PDEs are able to exert tight regulation over these important intracellular signaling cascades. Previously, PDEs have been implicated in learning and memory, as well as in mood disorders, such as anxiety and depression. PDE2 is of special interest due to its high level of expression in the forebrain, specifically in the isocortex, entorhinal cortex, striatum, hippocampus, amygdala, and medial habenula. Many of these brain regions are considered participants of the limbic system, which is known as the emotional regulatory center of the brain, and is important for modulating emotion and long-term memory. Therefore, PDE2s coincidental expression in these areas suggests an important role for PDE2 in these behaviors, and researchers are continuing to uncover the complex connections. It was shown that PDE2 inhibitors have pro-cognitive effects in tests of memory, including the object recognition test. PDE2 inhibitors are also protective against cognitive deficits in various models of cognitive impairment. Additionally, PDE2 inhibitors are protective against many different forms of stress-induced anxiety-like and depression-like behaviors. Currently, there is a great need for novel therapeutics for the treatment of mood and cognitive disorders, especially anxiety and depression, and other neurodegenerative diseases, such as Alzheimer's disease, and PDE2 is emerging as a viable target for future drug development for many of these diseases.

The temperament dimension of harm avoidance defines an individual's biological tendency to exhibit altering levels of anxious, inhibiting, and cautious behavior. High harm avoidance and anxiety are highly comorbid, likely due to activity in similar neural circuitries involving the dorsal raphe nucleus. Despite the many investigations that have explored personality factors and brain function, none have determined the influence of ongoing activity within dorsal raphe networks on harm avoidance. The aim of this study was to explore such a relationship. In 62 healthy subjects, a series of 180 functional magnetic resonance images covering the entire brain were collected, and each subject completed the 240-item TCI-R questionnaire. Independent component analyses were performed to define the dorsal raphe network and then to determine the regions significantly correlated with harm avoidance. The independent component analyses revealed three signal intensity fluctuation maps encompassing the dorsal raphe nucleus, showing interactions with regions of the amygdala, hippocampus, nucleus accumbens, and prefrontal, insular, and cingulate cortices. Within these systems, the resting signal intensity was significantly coupled to harm avoidance in the bilateral basal amygdala, bilateral ventral hippocampus, bilateral insula, bilateral nucleus accumbens, and medial prefrontal cortex. Note that we could not measure serotonergic output, but instead measured signal changes in the dorsal raphe that likely reflect synaptic activity. These data provide evidence that at rest, signal intensity fluctuations within the dorsal raphe networks are related to harm avoidance. Given the strong relationship between harm avoidance and anxiety-like behaviors, it is possible that ongoing activity within this identified neural circuitry can contribute to an individual developing anxiety disorders.

Effects of blockage of central galanin receptors on anxiety manifestations were studied in rats with psychogenic trauma. Psychogenic trauma was modeled by exposure of a group of rats to the situation when the partner was killed by a predator. Antagonist of galanin receptors was intranasally administered before stress exposure. Animal behavior was evaluated using the elevated-plus maze test, free exploratory paradigm, and open-field test. Psychogenic trauma was followed by an increase in anxiety level and appearance of agitated behavior. Blockage of galanin receptors aggravated behavioral impairment, which manifested in the pathological anxious reactions - manifestations of hypervigilance and hyperawareness. The results suggest that endogenous pool of galanin is involved into prevention of excessive CNS response to stressful stimuli typical of posttraumatic stress disorder.

Background: Despite the high use of antidepressants (ADs) among the elderly, there is limited information about the prescribing pattern of these drugs in the Italian elderly population. The aim of this study was to analyze the trend in the use of ADs in the Italian elderly patients in the years 2003-2009, and specifically, to evaluate rates and predictors of AD treatment discontinuation in depressed older patients., Methods: The nationwide general practice Health Search Database (HSD) was used to identify AD users aged 65 years old and over from 2003 to 2009. ADs were categorized as (1) selective serotonin reuptake inhibitors (SSRIs); (2) serotonin-norepinephrine reuptake inhibitors (SNRIs); (3) tricyclic antidepressants (TCAs); (4) noradrenergic and specific serotonergic antidepressants (NaSSAs); and (5) other ADs. Incidence and prevalence of AD use per 1,000 inhabitants was calculated by drug class and single compound. We also measured rates and predictors of AD discontinuation (i.e., treatment gap ≥ 60 days) during the first year of therapy., Results: Overall, 39,557 AD users ≥65 years (17 % of the total HSD elderly population) were included in the study. SSRIs were increasingly and most frequently prescribed ADs (102.7-195.3 per 1,000 over seven years). The most common indications for AD use were depression and anxiety. Overall, 14 % of AD users continued their AD medication without treatment gaps, 27 % were intermittent AD users and 58 % discontinued their ADs during the first year of follow-up. Specific AD classes such as TCAs and 'other ADs were found to be predictors of discontinuation. In depressed patients, the use of NaSSas, TCAs and 'other ADs as well the concomitant use of >5 drugs (other than ADs) and living in Southern Italy were more likely to predict discontinuation., Conclusion: ADs, especially SSRIs, are widely and increasingly prescribed in elderly Italian patients in recent years. The observed high AD discontinuation rates are likely to impact the achievement of a therapeutic endpoint in depressed patients. Patients who are at high risk of AD discontinuation such as those receiving multi-drug therapy or living in Southern Italy should be monitored more closely to improve benefits of AD treatments.

This study evaluated patients' and physicians' characteristics associated with the purchase of benzodiazepines by older primary care patients in Israel. The analytic sample consists of those 6,421 patients age 65 and older. We used multi-level analysis with whether or not benzodiazepines were purchased at least once between June 2005 and 2007 as an outcome. We also evaluated patients' and physicians' characteristics associated with the purchase of benzodiazepines for 6 months or longer. Almost half the sample (41.5%) purchased benzodiazepines at least once during the study period and more than half (54.5%) of those purchasing benzodiazepines had a continued purchase for 6 months or longer. Physicians' characteristics explained only a small portion of the variance associated with purchasing, whereas patients' demographic and clinical characteristics were associated with purchasing. Any intervention to improve the use of benzodiazepines should be directed at both patients and physicians.

Purpose: Our purpose was to explore antidepressant drug (AD) prescribing patterns in Italian primary care., Methods: Overall, 276 Italian general practitioners (GPs) participated in this prospective study, recruiting patients >18 years who started AD therapy during the enrolment period (January 2007 to June 2008). During visits at baseline and 3, 6, and 12 months, data about patients' characteristics and AD treatments were collected by the GPs. Discontinuation rate among new users of AD classes [i.e., selective serotonin reuptake inhibitors (SSRI); tricyclics (TCAs); other ADs) were compared. Logistic regression analyses were performed to identify predictors of AD discontinuation., Results: SSRIs were the most frequently prescribed ADs (N = 1,037; 75.3 %), especially paroxetine and escitalopram. SSRIs were more likely to be prescribed because of depressive disorders (80 %), and by GPs (51.1 %) rather than psychiatrists (31.8 %). Overall, 27.5 % (N = 378) of AD users discontinued therapy during the first year, mostly in the first 3 months (N = 242; 17.6 %), whereas 185 (13.4 %) were lost to follow-up. SSRI users showed the highest discontinuation rate (29 %). In patients with depressive disorders, younger age, psychiatrist-based diagnosis, and treatment started by GPs were independent predictors of SSRI discontinuation., Conclusions: In Italy, ADs-especially SSRIs-are widely prescribed by GPs because of depressive/anxiety disorders. Active monitoring of AD users in general practice might reduce the AD discontinuation rate.

Background: Generalized Anxiety Disorder (GAD) has been described in community studies as a frequent and costly high utilizer group in the primary care sector. Administrative data supporting this observation are lacking so far., Methods: This paper reports utilization and prescription data of a nationally representative sample of over 900 primary care physicians, over 75 million prescriptions and 12-month utilization and prescription patterns of n = 3,340 GAD patients.These are compared to a matched control group without GAD, and without any anxiety or depressive disorder (n = 3,340)., Results: GAD patients in comparison to the matched controls revealed: (1) 2-fold increased primary care, (2) almost 3-fold specialist referrals, (3) almost 2-fold increased overall prescription rates, and (4) 3.5-fold increased sick certificates. However, only 58.3% of GAD patients were treated with any psychotropic medication., Discussion: The data of this administrative-epidemiological cohort study support strongly the view that GAD ranks among the most costly high utilizer patient group in primary care in Germany. However, they are rarely treated according to evidence-based guidelines. The paper discusses these findings by suggesting that comorbid conditions might be a barrier for primary care physicians to initiate existing, more appropriate state of the art treatments.

There are conflicting results from behavioural studies regarding whether the activation or inhibition of the cGMP-nitric oxide (NO) pathway induces anxiolytic-like behaviour. Sildenafil, an inhibitor of cGMP-selective phosphodiesterase-5, increases anxiety acutely, but previous evidence suggests that its chronic administration may be anxiolytic, and could involve a cholinergic interaction. We used the Flinders Sensitive Line (FSL) rat, a genetic model of depression that presents with increased anxiety- and depression-like behaviour, to investigate the action of chronic treatment with the PDE5 inhibitors sildenafil or tadalafil, with/without atropine on social interaction behaviour, a correlate for anxiety. Fluoxetine was used as positive control, with validation performed using Flinders Resistant Line (FRL) rats. In order to relate behavioural changes to brain penetration, we determined the concentration of sildenafil in cortex and hippocampus of rats following the schedule above using LC-MS/MS. FSL rats displayed significantly reduced social interactive behaviour than FRL rats, while sildenafil, tadalafil, and fluoxetine significantly reversed these deficits. Atropine did not exert effects on social interactive behaviour, nor did it modulate the effects of sildenafil or tadalafil. Sildenafil was present in cortex and hippocampus regions in lower nanomolar concentrations after chronic treatment, in agreement with the binding to PDE5 required for pharmacological effects. This study emphasizes the complicated regulation of anxiety by the cGMP-NO system, and provides supporting evidence for an anxiolytic action after the chronic activation of this pathway. As far as we know this is also the first report to formally demonstrate that sildenafil effectively crosses the blood-brain barrier to elicit central effects.

The efficiency and safety of tenoten for anxiety and depression disorders in epileptics has been demonstrated. The drug does not change the incidence and severity of epileptic episodes, does not deteriorate the course of the underlying disease, and can be well combined with anticonvulsants. The results indicate the efficiency of tenoten used to arrest the anxio-depressive disorders in epilepsy.

Little is known about the biopsychosocial determinants that predict postpartum treatment outcome for mood and anxiety disorders. Postpartum mood and anxiety symptoms and psychosocial/biological variables were recorded for 8 months of 22 women treated with antidepressants during pregnancy. Depression scores decreased by 58%, whereas anxiety scores decreased by 35%. Family history of psychiatric illness and prior psychiatric illness unrelated to pregnancy predicted depressive treatment outcome, and sexual abuse history and prior psychiatric illness unrelated to pregnancy predicted anxiety outcome. Biological and psychosocial variables predicted pharmacological treatment outcome in postpartum-depressed and anxious women.

Purpose: In a recent meta-analysis of 38 double-blind randomized controlled trials (RCTs) comparing pregabalin (PGB) to placebo, we found 20 adverse events (AEs) to be significantly associated with PGB treatment. In the present study, we evaluated whether the incidence of these 20 AEs differs across distinct disorders in which PGB was investigated., Methods: Among the 38 previously identified RCTs of PGB, we selected only those including a PGB 600 mg/day arm and subsequently classified them into four distinct groups according to the disorder in which PGB was investigated: (1) drug-resistant partial epilepsy, (2) psychiatric disorders, (3) fibromyalgia, and (4) neuropathic pain. We used risk differences (RDs) to quantify the placebo-corrected proportion of subjects discontinuing PGB due to intolerable AEs and to determine the placebo-corrected incidence of each of the 20 PGB AEs across the four disorders., Results: Twenty-two RCTs were included in this study. Neither the proportion of subjects discontinuing PGB due to intolerable AEs nor the incidence of PGB AEs (with the exception of ataxia) differed significantly across the four disorders. Ataxia was more common in drug-resistant partial epilepsy compared to fibromyalgia. When limiting analyses to subjects on placebo, most vestibulo-cerebellar AEs (ataxia, diplopia, and blurred vision) were found to be more common in drug-resistant partial epilepsy compared to all other disorders. Diplopia and blurred vision were more common in epilepsy than in neuropathic pain; and ataxia had a higher incidence in epilepsy than in anxiety disorder and fibromyalgia. Among other CNS AEs, somnolence was more common in epilepsy compared to neuropathic pain and in anxiety disorders alone compared to neuropathic pain and fibromyalgia. Asthenia was also more common in epilepsy than in neuropathic pain and fibromyalgia., Conclusions: Although drug-resistant partial epilepsy is associated with a higher probability of developing vestibulo-cerebellar AEs, the risk for PGB toxicity does not differ across distinct disorders.

The amino-terminal pro-brain natriuretic peptide (NT-proBNP) is released into the plasma predominantly from ventricular cardiomyocytes, particularly in patients with chronic cardiac diseases, although small amounts are detectable in the plasma of healthy subjects. While NT-proBNP has been widely exploited in human medicine, limited literature is available related to its characterization in veterinary medicine (e.g., correlation with damage and specificity) and, particularly, in the context of preclinical drug safety assessment. This paper describes the analytical performance characteristics and the biological variability of NT-proBNP in male beagle dogs by using a commercially available enzyme-linked immunosorbent assay. Male beagle dogs were treated with Casopitant, an NK1 receptor antagonist under development for depression and anxiety, which, when administered chronically to dogs, caused cardiac toxicity. Heart weight increase, myocardial necrosis, degeneration, and inflammation associated with high serum levels of cardiac troponin I characterized the end stage pathology observed in dogs treated orally at 40 mg/kg for 39 weeks. Based on these data, ad hoc studies were designed in order to evaluate the possible relationship between NT-proBNP serum levels and both standard toxicology endpoints, such as the organ weight and histology, as well as nonstandard endpoints such as macroscopic morphometry and echocardiography. Early changes of NT-proBNP serum levels were observed following 2 weeks of treatment onward, preceding most, if not all of the anatomical and functional changes. The results obtained demonstrate that NT-proBNP acts as an early biomarker of cardiac changes, representing a sensitive and predictive marker of drug-induced cardiac liability.

Our objective was to evaluate the effect of stress-related dose of substance P (SP) on the in vitro proliferation and cytokine production in polyclonally activated T cells from healthy individuals or individuals with generalized anxiety disorder (GAD). Our results demonstrated that cell cultures from GAD group proliferated less following T cell activation, as compared with control group. The addition of SP enhanced, while the glucocorticoid (GC) reduced, the proliferative response in activated cell cultures from healthy but not from GAD individuals. The cytokine profile in GAD individuals revealed Th1 and Th2 deficiencies were associated with dominate Th17 phenotype which was enhanced by SP. Differently from control, the production of Th17 cytokines in GAD individuals was not affected by GC. In conclusion, our results show that complex T cell functional dysregulation in GAD individuals is significantly amplified by SP. These immune abnormalities can have impact in increasing the susceptibility to infectious diseases and inflammatory/autoimmune disorders in anxious individuals.

It has been suggested that antidepressants, including the selective serotonin reuptake inhibitors have neurotrophic effects. Nevertheless, the impact of treatment with a selective serotonin re-uptake inhibitor on regional brain volumes in social anxiety disorder has not been studied. 11 subjects with social anxiety disorder completed magnetic resonance imaging both before and after 12-weeks of treatment with 20 mg/day escitalopram. No increases in structural grey matter were found, but there were decreases in bilateral superior temporal cortex, vermis and the left cerebellum volumes following 12 weeks of treatment with escitalopram. These preliminary findings require replication to determine their reliability, and extension to determine whether or not they are disorder specific.

Generalized anxiety disorder (GAD) is common in community and clinical settings. The individual and societal burden associated with GAD is substantial, but many of those who could benefit from treatment are not recognized or treated. Recent evidence-based guidelines for the pharmacological management of patients with GAD have recommended initial treatment with either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), on the basis of their proven efficacy and reasonable tolerability in randomized placebo-controlled trials. However, there is much room for improvement in both the efficacy and the tolerability of treatment. Response rates to first-line treatment can be disappointing and it is hard to predict reliably which patients will respond well and which will have only a limited treatment response. Many patients worry about becoming dependent on medication, a substantial proportion experience troublesome adverse effects, and these problems limit the effectiveness of pharmacological treatments in clinical practice. The relative lack of longitudinal studies of clinical outcomes in GAD, and the small number of placebo-controlled relapse prevention studies lead to uncertainty about the optimal duration of treatment after a satisfactory initial response. There have been few investigations of the further management of patients who have not responded to first-line treatment and there is a pressing need for further augmentation studies in patients who have not responded to an SSRI or SNRI, or to other initial pharmacological approaches. Future treatment guidelines for GAD will be influenced by emerging data for established and novel pharmacological approaches, and possibly through the more accurate identification of certain patient subgroups who are likely to respond preferentially to particular interventions.

Psychiatric and neurological disorders are linked to changes in synaptic excitatory processes with a key role for glutamate, that is, the most abundant excitatory amino-acid. Molecular cloning of the metabotropic glutamate (mGlu) receptors has led to the identification of eight mGlu receptors, which, in contrast to ligand-gated ion channels (responsible for fast excitatory transmission), modulate and fine-tune the efficacy of synaptic transmission. mGlu receptors are G protein-coupled and constitute a new group of "drugable" targets for the treatment of various CNS disorders. The recent discovery of small molecules that selectively bind to receptors of Groups I (mGlu1 and mGlu5) and II (mGlu2 and mGlu3) allowed significant advances in our understanding of the roles of these receptors in brain function and dysfunction including anxiety. Although investigation of the role of the Group III (mGlu4, 6, 7, and 8) receptors is less advanced, the generation of genetically manipulated animals and recent advances in the identification of subtype-selective compounds have revealed some first insights into the therapeutic potential of this group of receptors.

Antidepressant drug treatment is the clinical standard of care for all types of anxiety disorders. Broad efficacy of selective serotonin reuptake inhibitors suggests the importance of enhanced serotonergic function of the anxiolytic properties of current antidepressants. However, analysis of the preclinical evidence indicates that most conventional "anxiolytic" drug tests are not sensitive to antidepressants. Such dissociation is not surprising because of the traditional approach to validation of preclinical tests that is to a large extent based on establishing face validity as well as sensitivity to benzodiazepine anxiolytics. The present review argues for extending the cognitive model of antidepressant drug action to cover their anxiolytic properties as well. Such an approach is based on ambiguity or uncertainty in a broad sense as the hallmark of human stress that has different expressions ready for experimental modeling. These possibilities include schedule-induced behaviors that are directly based on intermittent reinforcement, conditioning to ambiguous stimuli, social stress where agonistic confrontations are possible but not predictable or controlled by the subject, and an even larger class of behaviors that are critically dependent on the inhibition of the prepotent responses in exchange for the ambiguous possibility of a later gain in reinforcement. Interestingly, in all these cases, antidepressant drug treatment is clearly effective in preclinical laboratory settings. One of the cognitive functions that appears to be affected by antidepressant drugs is inhibitory control. Inhibition of prepotent responding has beneficial effects in the "uncertainty" stress situations discussed above and therefore it is this cognitive function that may be critical for anxiolytic effects of antidepressants and novel anxiolytic drug development.

Nonselective benzodiazepines exert their pharmacological effects via GABAA receptors containing either an alpha1, alpha2, alpha3, or alpha5 subunit. The use of subtype-selective tool compounds along with transgenic mice has formed the conceptual framework for defining the requirements of subtype-selective compounds with potentially novel pharmacological profiles. More specifically, compounds which allosterically modulate the alpha2 and/or alpha3 subtypes but are devoid of, or have much reduced, effects at the alpha1 subtype are hypothesized to be anxioselective (i.e., anxiolytic but devoid of sedation). Accordingly, three compounds, MRK-409, TPA023 and TPA023B, which selectively potentiated the effects of GABA at the alpha2 and alpha3 compared to alpha1 subtypes were progressed into man. All three compounds behaved as nonsedating anxiolytics in preclinical (rodent and primate) species but, surprisingly, MRK-409 produced sedation in man at relatively low levels of occupancy (< 10%). This sedation liability of MRK-409 in man was attributed to its weak partial agonist efficacy at the alpha1 subtype since both TPA023 and TPA023B lacked any alpha1 efficacy and did not produce overt sedation even at relatively high levels of occupancy (> 50%). The anxiolytic efficacy of TPA023 was evaluated in Generalized Anxiety Disorder and although these clinical trials were terminated early due to preclinical toxicity issues, the combined data from these incomplete studies demonstrated an anxiolytic-like effect of TPA023. This compound also showed a trend to increase cognitive performance in a small group of schizophrenic subjects and is currently under further evaluation of its cognition-enhancing effects in schizophrenia as part of the TURNS initiative. In contrast, the fate of the back-up clinical candidate TPA023B has not been publicly disclosed. At the very least, these data indicate that the pharmacological profile of compounds that differentially modulate specific populations of GABAA receptors is distinct from classical benzodiazepines and should encourage further preclinical and clinical investigation of such compounds, with the caveat that, as exemplified by MRK-409, the preclinical profile might not necessarily translate into man.

Animal models of anxiety attempt to represent some aspect of the etiology, symptomatology, or treatment of human anxiety disorders, in order to facilitate their scientific study. Within this context, animal models of anxiolytic drug action can be viewed as treatment models relevant to the pharmacological control of human anxiety. A major purpose of these models is to identify novel anxiolytic compounds and to study the mechanisms whereby these compounds produce their anxiolytic effects. After a critical analysis of "face," "construct," and "predictive" validity, the biological context in which animal models of anxiety are to be evaluated is specified. We then review the models in terms of their general pharmacological profiles, with particular attention to their sensitivity to 5-HTIA agonists and antidepressant compounds. Although there are important exceptions, most of these models are sensitive to one or perhaps two classes of anxiolytic compounds, limiting their pharmacological generality somewhat, but allowing in depth analysis of individual mechanisms of anxiolytic drug action (e.g., GABAA agonism). We end with a discussion of possible sources of variability between models in response to 5-HTIA agonists and antidepressant drugs.