Exposure of pregnant rats to stress and/or sertraline: Side effects on maternal health and neurobehavioral development of male offspring.

AIMS: Sertraline (SE) is one of the most prescribed medications for treating gestational depression, anxiety and stress. However, little is known about its effects on nervous-system development in offspring. Therefore, this study investigated the somatic, reflex and neurobehavioral development of rats exposed to SE during pregnancy, associated or not with stress. MAIN METHODS: Pregnant Wistar rats were assigned to the following groups (n = 10-8 rats/group): CO - control animals administered filtered water by gavage; SE - animals administered 20 mg/kg SE by gavage; ST - animals subjected to restraining stress and administered filtered water; ST/SE - animals subjected to restraining stress and administered 20 mg/kg SE. The treatment was administered between gestational days (GD) 13 to 20. Somatic and reflex developments were investigated in the male offspring from postnatal day (PND) 1 to 21. The elevated plus maze was performed on PND 25 and 80. The open field and light/dark box test were performed on PND 90 and 100, respectively. KEY FINDINGS: Body weight reduction and vaginal bleeding were observed in pregnant rats exposed to SE. The male offspring of the SE group showed delay in incisor eruption, fur development and negative geotaxis. In addition, the SE group was less exploratory (anxious personality) compared to the CO and ST groups. SIGNIFICANCE: The results obtained in the present study demonstrate that sertraline not only impairs maternal health, but also, associated or not with stress, can compromise the somatic, reflex and neurobehavioral development of male rats.

Efficacy of antidepressant drugs in the treatment of depression in Alzheimer disease patients: A systematic review and network meta-analysis.

BACKGROUND: Depression is considered as one of the most common neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) patients. Prescription of antidepressants is a current clinical practice well-established as the first-line treatment for such patients. Our study was aimed at systematically examining the evidence on the efficacy of antidepressants in the treatment of depression in AD patients. METHODS: We conducted a network meta-analysis of randomized controlled trials retrieved by systematic search of the Cochrane Central Register of Controlled Trials, PubMed, Embase, and CNKI databases. Primary outcomes included mean depression score and safety. Secondary outcomes were cognition. The surface under the cumulative ranking curve was performed to estimate a ranking probability for different treatments. RESULTS: A total of 25 studies including 14 medications met the inclusion criteria. Compared with placebo, only mirtazapine (standard mean deviation [SMD], -1.94; 95% confidence interval [CI], -3.53 to -0.36; p < 0.05) and sertraline (SMD, -1.16; 95% CI, -2.17 to -0.15; p < 0.05) showed a slightly better effect in treating symptoms of depression. Clomipramine increased risk of adverse events than placebo (odds ratio, 3.01; 95% CI, 1.45 to 4.57; p < 0.05). In terms of cognitive function, there was no statistically significant difference between antidepressants and placebo. CONCLUSION: Overall, in the short-term treatment, these data suggest that commonly used antidepressants sertraline and mirtazapine should be considered as an alternative treatment for depression in AD patients. However, more high-quality trials with large samples and longer following-up are proposed.

The Role of Serotonin in Breast Cancer Stem Cells.

Breast tumors were the first tumors of epithelial origin shown to follow the cancer stem cell model. The model proposes that cancer stem cells are uniquely endowed with tumorigenic capacity and that their aberrant differentiation yields non-tumorigenic progeny, which constitute the bulk of the tumor cell population. Breast cancer stem cells resist therapies and seed metastases; thus, they account for breast cancer recurrence. Hence, targeting these cells is essential to achieve durable breast cancer remissions. We identified compounds including selective antagonists of multiple serotonergic system pathway components required for serotonin biosynthesis, transport, activity via multiple 5-HT receptors (5-HTRs), and catabolism that reduce the viability of breast cancer stem cells of both mouse and human origin using multiple orthologous assays. The molecular targets of the selective antagonists are expressed in breast tumors and breast cancer cell lines, which also produce serotonin, implying that it plays a required functional role in these cells. The selective antagonists act synergistically with chemotherapy to shrink mouse mammary tumors and human breast tumor xenografts primarily by inducing programmed tumor cell death. We hypothesize those serotonergic proteins of diverse activity function by common signaling pathways to maintain cancer stem cell viability. Here, we summarize our recent findings and the relevant literature regarding the role of serotonin in breast cancer.

The administration of sertraline plus naltrexone reduces ethanol consumption and motivation in a long-lasting animal model of post-traumatic stress disorder.

This study was aimed to evaluate the effects of sertraline (STR) and/or naltrexone (NTX) on ethanol consumption and motivation in an animal model of post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD). Male C57BL/6J mice were submitted to an intermittent and progressively increasing stressful stimuli simulating PTSD behavioural features. Behavioural alterations were explored by the fear conditioning (FC), novelty suppressed feeding test (NSFT) and acoustic startle response (ASR) paradigms. Afterwards, mice were evaluated in the voluntary ethanol consumption (VC) and the oral ethanol self-administration (OEA) paradigms. The effects of STR (10 mg/kg) and/or NTX (0.7 mg/kg) on ethanol consumption and motivation were analysed in the OEA. Furthermore, relative gene expression analyses of tyrosine hydroxylase (Th), mu-opioid receptor (Oprm1) and 5-hydroxitryptamine transporter (Slc6a4) were performed in the ventral tegmental area (VTA), nucleus accumbens (NAcc) and dorsal raphe nucleus (DR), respectively. PTSD-like mice presented increased fear-related memory, anxiety-like behaviours, and startle response, as well as enhanced ethanol consumption and motivation in the VC and OEA paradigms. Interestingly, STR plus NTX combination significantly reduced ethanol intake and motivation in the OEA. Gene expression analyses revealed reduced Th and Oprm1 whereas Slc6a4 gene expression increased in PTSD-like mice. STR and/or NTX modulated Th and Slc6a4 gene expression changes in PTSD-like mice. Furthermore, NTX increased Oprm1 gene expression revealing a synergistic action when combined with STR. These results provide evidence about the efficacy of the STR plus NTX to attenuate ethanol reinforcement and motivation in an animal model of PTSD and AUD dual pathology.

Psychotropic drugs upregulate aquaporin-2 via vasopressin-2 receptor/cAMP/protein kinase A signaling in inner medullary collecting duct cells.

Psychotropic drugs may be associated with hyponatremia, but an understanding of how they induce water retention in the kidney remains elusive. Previous studies have postulated that they may increase vasopressin production in the hypothalamus without supporting evidence. In this study, we investigated the possibility of drug-induced nephrogenic syndrome of inappropriate antidiuresis using haloperidol, sertraline, and carbamazepine. Haloperidol, sertraline, or carbamazepine were treated in inner medullary collecting duct (IMCD) suspensions and primary cultured IMCD cells prepared from male Sprague-Dawley rats. The responses of intracellular cAMP production, aquaporin-2 (AQP2) protein expression and localization, vasopressin-2 receptor (V2R) and AQP2 mRNA, and cAMP-responsive element-binding protein (CREB) were tested with and without tolvaptan and the protein kinase A (PKA) inhibitors H89 and Rp-cAMPS. In IMCD suspensions, cAMP production was increased by haloperidol, sertraline, or carbamazepine and was relieved by tolvaptan cotreatment. In primary cultured IMCD cells, haloperidol, sertraline, or carbamazepine treatment increased total AQP2 and decreased phosphorylated Ser261-AQP2 protein expression. Notably, these responses were reversed by cotreatment with tolvaptan or a PKA inhibitor. AQP2 membrane trafficking was induced by haloperidol, sertraline, or carbamazepine and was also blocked by cotreatment with tolvaptan or a PKA inhibitor. Furthermore, upregulation of V2R and AQP2 mRNA and phosphorylated CREB was induced by haloperidol, sertraline, or carbamazepine and was blocked by tolvaptan cotreatment. We conclude that, in the rat IMCD, psychotropic drugs upregulate AQP2 via V2R-cAMP-PKA signaling in the absence of vasopressin stimulation. The vasopressin-like action on the kidney appears to accelerate AQP2 transcription and dephosphorylate AQP2 at Ser261.NEW & NOTEWORTHY It is unclear whether antipsychotic drugs can retain water in the kidney in the absence of vasopressin. This study demonstrates that haloperidol, sertraline, and carbamazepine can produce nephrogenic syndrome of inappropriate antidiuresis because they directly upregulate vasopressin-2 receptor and aquaporin-2 (AQP2) via cAMP/PKA signaling. We showed that, in addition to AQP2 trafficking, AQP2 protein abundance was rapidly increased by treatment with antipsychotic drugs in association with dephosphorylation of AQP2 at Ser261 and accelerated AQP2 transcription.

The application of precision dosing in the use of sertraline throughout pregnancy for poor and ultrarapid metabolizer CYP 2C19 subjects: A virtual clinical trial pharmacokinetics study.

Sertraline is known to undergo changes in pharmacokinetics during pregnancy. CYP 2C19 has been implicated in the interindividual variation in clinical effect associated with sertraline activity. However, knowledge of suitable dose titrations during pregnancy and within CYP 2C19 phenotypes is lacking. A pharmacokinetic modeling virtual clinical trials approach was implemented to: (i) assess gestational changes in sertraline trough plasma concentrations for CYP 2C19 phenotypes, and (ii) identify appropriate dose titration strategies to stabilize sertraline levels within a defined therapeutic range throughout gestation. Sertraline trough plasma concentrations decreased throughout gestation, with maternal volume expansion and reduction in plasma albumin being identified as possible causative reasons. All CYP 2C19 phenotypes required a dose increase throughout gestation. For extensive metabolizer (EM) and ultrarapid metabolizer (UM) phenotypes, doses of 100-150 mg daily are required throughout gestation. For poor metabolizers (PM), 50 mg daily during trimester 1 followed by a dose of 100 mg daily in trimesters 2 and 3 are required.

Therapeutic effects of sertraline on improvement of Ovariectomy-induced decreased spontaneous activity in mice.

We have already reported that ovariectomized (OVX) rats reduced the spontaneous activity during the dark period due to the decease of serotonin release in the amygdala. In this study, we examined the potential of sertraline, a selective serotonin reuptake inhibitor, on the recovery of less spontaneous activity seen in mice with OVX-induced despair-like behaviors. Female 9-week old ICR mice were underwent either OVX or sham surgery. Sertraline (10 mg/kg/day, s.c.) or saline were started to administer to each group for 8 weeks (6 times/week) from the 8th week after OVX. Each spontaneous activity of mouse was evaluated during the dark period (19:00-07:00) using an infrared sensor. Moreover, mRNA expression levels of tryptophan hydroxylase (TPH) and X-box binding protein 1 (XBP1) were measured in the hippocampus and prefrontal cortex using by a real-time PCR method. We found out that the OVX-induced despair-like behaviors were improved by the continuous administration of sertraline. After treatment of OVX, our real-time PCR data showed that sertraline significantly suppressed the upregulation of XBP1 expression levels in both hippocampus and prefrontal cortex, although this suppression of the downregulation of TPH expression levels was seen in only hippocampus. These results suggest that sertraline improves the decrease in spontaneous activity induced by OVX assessed by the hippocampus suppressing decreased serotonin synthesis in the serotonergic neuron.

Comparing Medications for DSM-5 PTSD in Routine VA Practice.

OBJECTIVE: Fluoxetine, paroxetine, sertraline, topiramate, and venlafaxine have previously shown efficacy for posttraumatic stress disorder (PTSD). One prior study using US Department of Veterans Affairs (VA) medical records data to compare these agents found no differences in symptom reduction in clinical practice. The current study addresses several weaknesses in that study, including limited standardization of treatment duration, inability to account for prior treatment receipt, use of an outdated symptomatic assessment for PTSD, and lack of functional outcome. METHODS: A total of 834 VA outpatients were identified with DSM-5 clinical diagnoses of PTSD between October 2016 and March 2018 who initiated one of the medications and met prespecified criteria for treatment duration and dose, combined with baseline and endpoint DSM-5 PTSD Checklist (PCL-5) measurements. Twelve-week acute-phase changes in PCL-5 score and remission of PTSD symptoms were compared among patients receiving the different medications, as was use of acute psychiatric services in the subsequent 6-month continuation phase. RESULTS: In the acute phase, patients improved by a mean of 6.8-10.1 points on the PCL-5 and 0.0%-10.9% achieved remission of PTSD symptoms. Those taking venlafaxine were significantly more likely to achieve remission (P = .008 vs fluoxetine and P < .0001 vs paroxetine, sertraline, and topiramate). In the continuation phase, there were no differences in acute psychiatric care use between medications. Those who continued their medication were less likely to use acute psychiatric services (HR = 0.55; P = .03). CONCLUSIONS: There may be an advantage to venlafaxine over other agents in achieving acute-phase remission for DSM-5 PTSD in routine clinical practice, but this finding requires further study. Regardless of the agent chosen, medication cessation during the continuation phase is associated with a higher risk of acute psychiatric care use.

Therapeutic drug monitoring is useful when pharmacogenetic assessment is unavailable: case report of delusional disorder / La monitorización terapéutica de fármacos es útil cuando la evaluación farmacogenética no está disponible: caso clínico de trastorno delirante

Antipsychotic plasma levels have been extensively used in the assessment of poor treatment response, lack of adherence and adverse events in delusional disorder. It has not been used as an indicator of metabolizer status, to determine whether a delusional disorder patient is a poor, intermediate, or ultra-rapid metabolizer of antipsychotics. Pharmacogenetic probes are, of course, the right method for the latter task, but they are not readily available for clinical use. We report the case of a 46-year-old woman with delusional disorder who developed unexpected adverse effects to treatment with relatively low dose risperidone and poor symptomatic response. Blood level monitoring indicated high levels of risperidone and a high concentration-to-dose ratio, which suggested accumulation of unmetabolized risperidone. Paradoxically, extrapyramidal side effects increased when, after reducing the risperidone dose, 5 mg/day of aripiprazole was added. Consequently, the patient was switched to olanzapine 5 mg/day. Sertraline 150 mg/day was later added for comorbid depression. A complete symptomatic response was achieved. Although other factors may well have been at play, this sequence of events suggests that the patient was a slow metabolizer of CYP2D6, which metabolizes both risperidone and aripiprazole. With pharmacogenetic assessment not available, therapeutic drug monitoring helped clinicians decide on appropriate management

Los niveles plasmáticos de antipsicóticos han sido extensamente utilizados para la evaluación de la pobre respuesta terapéutica, la falta de adherencia y los eventos adversos en pacientes con trastorno delirante. No han sido frecuentemente utilizados como indicadores del estado metabólico, para determinar si un paciente con trastorno delirante es metabolizador pobre, intermedio o metabolizador ultra-rápido de antipsicóticos. Los test de farmacogenética son, por supuesto, el método más idóneo para la última tarea, pero no son fáciles de obtener para su uso clínico. Reportamos el caso de una mujer de 46 años de edad con trastorno delirante que ha desarrollado efectos adversos inesperados con el tratamiento a dosis bajas de risperidona, y una pobre respuesta clínica. La monitorización de niveles plasmáticos indicó niveles elevados de risperidona y una ratio elevada concentración-dosis, que sugirió acumulación de risperidona no adecuadamente metabolizada. Paradójicamente, los efectos secundarios se incrementaron, cuando al reducir la dosis de risperidona, se añadió aripiprazol 5mg/día. Por ello, se realizó un cambio a olanzapina 5 mg/día. Se añadió sertralina 150 mg/día posteriormente para el tratamiento de síntomas depresivos comórbidos. Se alcanzó una respuesta clínica completa. A pesar de que otros factores pudieran haber contribuido a ello, la secuencia de eventos sugiere que la paciente pudiera ser metabolizadora lenta del CYP2D6, que metaboliza risperidona y aripiprazol. En caso de no disponibilidad de tests farmacogenéticos, la monitorización de niveles plasmáticos, ayudó a los clínicos a decidir el manejo apropiado del paciente

Hipofunción vestibular bilateral intercrítica en una paciente con migraña. Hacia la hipótesis integradora / Bilateral vestibular hypofunction occurring between migraine attacks: toward an integrative hypothesis

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Prolonged Exposure and Sertraline Treatments for Posttraumatic Stress Disorder Also Improve Multiple Indicators of Social Functioning.

Trauma survivors with posttraumatic stress disorder (PTSD) frequently also suffer from difficulties in social functioning that range across emotional, cognitive, and environmental domains. A detailed evaluation of the differential impacts of effective PTSD treatments on social functioning is needed. Men and women (N = 200) with chronic PTSD received 10 weeks of prolonged exposure (PE) or sertraline in a randomized clinical trial and were followed for 24 months. A secondary data analysis examined changes in social functioning with regard to fear of intimacy; receipt of social support; and distress, avoidance, and negative cognitions in social situations. Effects were examined between treatments over time, controlling for baseline functioning. There were large, durable improvements across all indices. Compared to sertraline, PE was more efficient at reducing fear of intimacy and distress from negative social cognitions by posttreatment, ds = 0.94-1.14. Patients who received sertraline continued to improve over the course of follow-up, ds = 0.54-1.17. The differential speed of therapeutic effects may argue for more direct mechanisms in cognitive behavioral interventions versus cascade effects in serotonin reuptake inhibitors. Notably, both treatments produced substantial social benefits for trauma survivors with social functioning difficulties, and effect sizes were comparable to typical reductions in PTSD, depression, and anxiety.

Population Pharmacokinetics of Sertraline in Healthy Subjects: a Model-Based Meta-analysis.

Sertraline pharmacokinetics is poorly understood and highly variable due to large between-subject variability with inconsistent reports for oral bioavailability. The study objective was to characterize sertraline pharmacokinetics by developing and validating a sertraline population pharmacokinetic (PK) model in healthy subjects using published clinical PK data. We carried a systematic literature search in PubMed in October 2015 and identified 27 pharmacokinetic studies of sertraline conducted in healthy adult subjects and reported in the English language. Sixty mean plasma concentration-time profiles made of 748 plasma concentrations following IV, single, and multiple oral doses ranging from 5 to 400 mg were extracted and analyzed for dose proportionality by a log-linear model and fitted to a 2-compartment pharmacokinetic model in NONMEM using a model-based meta-analysis (MBMA) approach. After a single oral dose, sertraline Cmax and AUC∞ increased with dose proportionally between 50 and 200 mg, and bioavailability increased nonlinearly with dose from 5 to 50 mg and plateaued afterwards while Tmax and t1/2 did not change with dose. Following multiple oral doses, Cmax and AUC∞ increased proportionally with dose across the entire dose range (5-200 mg) while bioavailability, Tmax, and t1/2 remained constant with dose. Sertraline absorption was time-dependent and best described by a sigmoidal Emax function of time after dose. Study findings indicate that sertraline PK is linear in healthy adult subjects at doses ≥ 50 mg, and exposures were nonlinear only after single oral doses < 50 mg likely due to reduced bioavailability.

Adjunctive sertraline for asymptomatic cryptococcal antigenemia: A randomized clinical trial.

Cryptococcal antigen (CrAg) screening in HIV-infected persons with CD4 < 100 cells/µl can reduce meningitis and death, yet preemptive fluconazole therapy fails in ∼25%. Sertraline has in vitro and in vivo activity against Cryptococcus and is synergistic with fluconazole in mice. We evaluated the efficacy and safety of sertraline in asymptomatic cryptococcal antigenemia. We conducted a randomized trial of asymptomatic CrAg-positive Ugandans from November 2017 to February 2018. All subjects received WHO standard therapy of fluconazole 800 mg for 2 weeks, then 400 mg for 10 weeks, then 200 mg through 24 weeks. Participants were randomized to receive adjunctive sertraline or placebo, given in once-weekly escalating 100 mg/day doses up to 400 mg/day, which was then given for 8 weeks, then tapered. The primary endpoint was meningitis-free 6-month survival. The data and safety monitoring board halted the trial after 21 subjects were enrolled due to safety concerns. Meningitis-free 6-month survival occurred in 9 of 11 of placebo participants and 10 of 10 of sertraline participants. However, seven serious adverse events (SAEs) occurred (n = 4 sertraline group; n = 3 placebo group). Three SAEs in the sertraline group presented with psychosis and aggressive behavioral changes with one meeting Hunter's criteria for serotonin syndrome while receiving 200 mg/day sertraline. Two transient psychoses were associated with antecedent fluconazole and sertraline interruption. The serotonin syndrome resolved within 1 day, but psychosis persisted for 4 months after sertraline discontinuation. Sertraline was associated with excess SAEs of psychosis. Due to early stopping, we were unable to determine any efficacy for cryptococcal antigenemia.

Aripiprazol intramuscular de liberación prolongada como potenciación de sertralina en una adolescente con Trastorno obsesivo-compulsivo. A propósito de un caso / Aripiprazole Long-Acting Intramuscular Injection Augmentation of Sertraline in Obsessive-Compulsive Disorder in Adolescence. A case report

El Trastorno obsesivo-compulsivo constituye una patología grave e incapacitante. El tratamiento de primera línea no consigue una remisión completa en casi la mitad de los pacientes. En adultos se ha demostrado la utilidad del tratamiento coadyuvante con aripiprazol en estos casos. En adolescentes la evidencia al respecto es escasa, aunque se han publicado algunos resultados prometedores. Tampoco se dispone de evidencia suficiente sobre la eficacia y seguridad de los antipsicóticos inyectables de liberación prolongada en población adolescente, por lo que sólo se recomiendan en trastornos psicóticos con respuesta insuficiente por falta de adherencia. Sin embargo, algunos autores proponen extender su utilización a otras patologías. Se presenta el caso de una paciente adolescente con trastorno obsesivocompulsivo resistente al tratamiento de primera línea, en la que la utilización coadyuvante de aripiprazol inyectable de liberación prolongada permite un buen control de la clínica obsesiva y contribuye a evitar nuevas descompensaciones

Obsessive-compulsive disorder is a severe and disabling pathology. First-line treatment does not achieve full remission in almost half of patients. In adults, the efficacy of the adjuvant treatment with aripiprazole has been demonstrated in these cases. There is not enough evidence in the adolescent population, although some promising results have been published. Scant evidence is available on the efficacy and safety of long-acting injectable antipsychotics in adolescents. Their use is recommended only in psychotic disorders with insufficient response due to lack of adherence. However, some authors suggest their use in other pathologies. The case of an adolescent patient with obsessive-compulsive disorder resistant to first-line treatment is presented. The adjuvant use of long-acting injectable aripiprazole allows for good control of the obsessive symptoms and helps prevent future episodes

The long and winding road of discontinuing long-term use of antidepressants: Learning from my experience.

WHAT IS KNOWN ON THE SUBJECT?: More people experience withdrawal symptoms when weaning off antidepressants than previously thought; particularly after taking them for a long time. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: I explore my own experience of weaning off antidepressants; detailing conflicting advice I have received from healthcare professionals, and the mental and physical withdrawal symptoms I experienced. I relate my experiences to a growing body of research, which have important implications for improving care. WHAT ARE THE IMPLICATIONS FOR MENTAL HEALTH NURSING?: Healthcare professionals should make patients aware of potential withdrawal symptoms they may experience before they wean off antidepressants; regularly review their progress; consider helping them access psychological support whilst weaning off; and engage in open and collaborative conversations with patients throughout. Clinical guidance needs to be updated to provide appropriate evidence-based information/advice/recommendations for how best to support patients when coming off of antidepressants. ABSTRACT: A significant proportion of the UK population are taking antidepressants, and have been taking them for at least a year. Clinical guidelines have controversially stated that withdrawal symptoms when weaning off antidepressants are mild and resolve after one week, with the proviso that they can be severe only if the drug is stopped abruptly. However, recent evidence suggests this is not the case. I describe my own experiences of tapering the dose of my antidepressants after several years of taking them. I describe my encounters with healthcare professionals throughout this period, detailing conflicting advice I have received, along with describing the mental and physical withdrawal symptoms I have experienced. My experiences relate to a growing body of research, which have important implications for improving care. Potential learning outcomes are that healthcare professionals should make patients aware of potential withdrawal symptoms they may experience before they wean off antidepressants; regularly review their progress; consider helping them access psychological support whilst weaning off; and engage in open and collaborative conversations with patients throughout the process. Clinical guidance needs to be updated to provide appropriate evidence-based information, advice, and recommendations for how best to support patients when coming off of antidepressants.

The Impact of Treatment Expectations on Exposure Process and Treatment Outcome in Childhood Anxiety Disorders.

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.