Effects of Selective Serotonin Reuptake Inhibitor Treatment on Blood Pressure in Resistant Hypertensive Patients with Anxiety Disorder

Objective: There are potential risks and benefits of combining benzodiazepine (BZD) and selective serotonin reuptake inhibitor (SSRI) therapy at anxiety disorder treatment onset. We investigated how often adolescents and young adults with anxiety disorders simultaneously initiate BZD treatment with SSRI treatment and examined whether SSRI treatment duration varies by simultaneous BZD initiation.Methods: In a United States commercial claims database (January 2008-December 2016), we identified adolescents (10-17 years) and young adults (18-24 years) with ICD-9-CM/ICD-10-CM anxiety disorder diagnoses initiating SSRI treatment, without past-year SSRI and BZD treatment. We defined simultaneous initiation as filling a new BZD prescription on the date of SSRI initiation. We estimated time to SSRI treatment discontinuation and used stabilized inverse probability of treatment weighting for adjusted estimates.Results: The study included 94,399 adolescents and 130,971 young adults initiating SSRI treatment with an anxiety disorder. Four percent of adolescents and 17% of young adults simultaneously initiated BZD treatment, varying by age, anxiety disorder, comorbidities, health care utilization, and provider type. Simultaneous BZD initiation among SSRI initiators declined from 2008 to 2016. SSRI treatment duration was similar in initiators of simultaneous therapy vs SSRI monotherapy: ≥ 6 months in adolescents (55% vs 56%, respectively) and in young adults (39% vs 40%). Nine percent of simultaneous initiators continued BZDs for ≥ 6 months.Conclusions: Simultaneous initiation of BZD and SSRI treatment is relatively common in young adults with anxiety disorders and was not associated with longer SSRI persistence. Given risks of BZD treatment, potential benefits and risks of adding a BZD at SSRI treatment initiation must be carefully weighed.

The Effects of Pharmacological Treatment on Functional Brain Connectome in Obsessive-Compulsive Disorder

Structural variations of neural regions implicated in fear responses have been well documented in the pathophysiology of anxiety and may play an important role in treatment response. We examined whether gray matter volume of three neural regions supporting fear and avoidance responses [bilateral amygdala, nucleus accumbens (NAcc), and ventromedial prefrontal cortex (PFC)] predicted cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitor (SSRI) treatment outcome in two independent samples of patients with anxiety disorders. Study 1 consisted of 81 adults with anxiety disorders and Study 2 included 55 children and adolescents with anxiety disorders. In both studies, patients completed baseline structural MRI scans and received either CBT or SSRI treatment. Clinician-rated interviews of anxiety symptoms were assessed at baseline and posttreatment. Among the adult sample, greater pre-treatment bilateral NAcc volume was associated with a greater reduction in clinician-rated anxiety symptoms pre-to-post CBT and SSRI treatment. Greater left NAcc volume also predicted greater decreases in clinician-rated anxiety symptoms pre-to-post CBT and SSRI treatment among youth with current anxiety. Across studies, results were similar across treatments, and findings were maintained when adjusting for patient's age, sex, and total intracranial brain volume. We found no evidence for baseline amygdala or ventromedial PFC volume serving as treatment predictors across the two samples. Together, these findings provide promising support for the role of NAcc volume as an objective marker of anxiety treatment improvement that spans across development. Future studies should clarify the specific mechanisms through which NAcc volume exerts its therapeutic effects.

Neural mechanisms and predictors of SSRI and CBT treatment of anxiety: A randomized trial focused on emotion and cognitive processing

Studies generally do not examine patients' prestroke depression diagnoses and treatments. To examine the association of depression diagnosis and prestroke and/or poststroke selective serotonin reuptake inhibitor (SSRI) treatment with poststroke mortality. We conducted a retrospective study of the medical records of a cohort of veterans with a stroke diagnosis between July 31, 2000, and September 30, 2001. Data regarding demographics, comorbidities, depression diagnosis, and treatment were abstracted from automated databases and electronic medical records for 6 months before and 1 year after the stroke index date. The survival rates of veterans who received an SSRI before and/or after the stroke were estimated using Kaplan-Meier survival analysis. Time-dependent Cox proportional hazards regression model was used to assess the association between risk factors and mortality. Among 870 veterans, 80 died less than 60 days after their stroke. Among the remaining 790, 12% died within 1 year, 26% died by the end of follow-up (May 1, 2007), and more than 62% were alive at the end of follow-up. Veterans were 3 times as likely to die if they had been treated for depression with an SSRI only before their stroke (hazard ratio [HR], 3.12; 95% CI 1.60 to 6.09). In the time-dependent model, SSRI treatment both before and after the stroke was protective compared with no SSRI treatment during the year following the stroke (HR 0.31; 95% CI 0.11 to 0.86). However, the survival curves crossed over and SSRI treatment before and after stroke conferred greater risk at the end of 7 years (HR 1.36; 95% CI 1.00 to 1.87). Depression diagnosis was associated with greater risk of mortality (HR 1.87; 95% CI 1.24 to 2.82). Poststroke SSRI treatment was associated with longer survival even though depression diagnosis was associated with earlier mortality in the unadjusted model. After a stroke, SSRI initiation or resumption of treatment should be considered as part of a medication therapy management service, especially if the patient has a history of depression or was taking an SSRI before the stroke.

Clopidogrel dose responsiveness, poststroke survival and SSRI treatment, and discontinuation of physician–pharmacist intervention

BackgroundBioimpedance has been shown to be a safe technique when used in a number of biomedical applications. In this study, we used the Electro Interstitial Scan (EIS) to perform bioimpedance measurements to follow up the efficacy of selective serotonin reuptake inhibitor (SSRI) treatment in subjects diagnosed to have major depressive disorder.MethodsWe recruited 59 subjects (38 women, 21 men) aged 17–76 (mean 47) years diagnosed with major depressive disorder by psychiatric assessment at the Botkin Hospital according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Baseline Clinical Global Impression scores and EIS (electrical conductivity and dispersion α parameter) measurements were done before starting SSRI therapy. Treatment follow-up was undertaken using EIS bioimpedance measurements and by treatment response based on the Hamilton Depression Scale and Clinical Global Impression, every 15 days for 60 days. At day 45, we classified the patients into two groups, ie, Group 1, including treatment responders, and Group 2, including nonresponders. At day 60, patients were classified into two further groups, ie, Group 3, comprising treatment responders, and Group 4, comprising nonresponders.ResultsComparing Group 1 and Group 2, electrical conductivity measurement of the pathway between the two forehead electrodes had a specificity of 72% and a sensitivity of 85.3% (P < 0.0001), with a cutoff >4.32. Comparing Group 3 and Group 4, electrical conductivity measurements in the same pathway had a specificity of 47.6% and a sensitivity of 76.3% (P < 0.16), with a cutoff >5.92. Comparing Group 1 and Group 2, the electrical dispersion α parameter of the pathway between the two disposable forehead electrodes had a specificity of 80% and a sensitivity of 85.2% (P < 0.0001) with a cutoff >0.678. Comparing Group 3 and Group 4, the electrical dispersion α parameter of the same pathway had a specificity of 100%, a sensitivity of 89.5% (P < 0.0001), and a cutoff >0.692.ConclusionElectrical conductivity measurement of the forehead pathway using EIS has a high specificity and sensitivity at day 45 when comparing treatment responders and nonresponders, but decreases at day 60. The EIS electrical dispersion α parameter of the forehead pathway has a high specificity and sensitivity at day 45 when comparing treatment responders and nonresponders, and increases at day 60. The EIS system may be a noninvasive, easily administered, low-cost technique that could be used as an adjunct to DSM-IV and Clinical Global Impression scores for monitoring of efficacy of treatment in patients with major depressive disorder.

Disclosure: L.P. Agnew: None. R. Domingues: None. A. Weichmann: None. L.L. Hernandez: None. Maternal mental health is critical for both mother and infant and often antidepressant therapy outweighs the potential risks of selective serotonin reuptake inhibitor (SSRI) treatment; however, SSRI use is associated with adverse neonatal outcomes. Preliminary work in our laboratory revealed placental apoptosis in pregnant dams treated with fluoxetine (FLX) and dams genetically deficient for the serotonin transporter gene. We hypothesize that SSRIs decrease placental blood flow, causing apoptosis and organ death via signaling through the serotonin 2A/2C receptors. Pregnant female C57BL6 mice were randomized to be treated daily, via I.P. injection, from E10-17.5 with saline (CON; n=6), 2 mg/kg FLX (n=5), or 2 mg/kg ketanserin plus 2 mg/kg FLX (n=5). On E17.5, using high-resolution ultrasound imaging, we identified the uterine artery, individual umbilical cords, and placental disc blood vessels. We calculated blood pressure, blood volume, blood flow rate, and heart rate in the uterine artery, umbilical cord, and placental disc. FLX (decreased blood volume in the uterine artery compared to ketanserin plus FLX (48.42 ± 18.26, 116.54 ± 45.25; p=0.0077), and decreased average (89.38 ± 31.50) and peak (130.36 ± 39.05) blood velocity in the uterine artery compared to ketanserin plus FLX average (162.76 ± 68.46; p=0.0322) and peak (236.77 ± 92.43; p=0.0242) blood velocity. FLX decreased average (0.04 + 0.02) and peak (0.07 ± 0.04) blood pressure in the uterine artery compared to ketanserin and FLX treated animals average (0.12 ± 0.10; p=0.0634) and peak (0.25 ± 0.19; p=0.0412) blood pressure. Ketanserin plus FLX (391 ± 38.29) decreased heart rate (BPM) in the placental disc compared to untreated controls (450.67 ± 26.08; p=0.0128). In the umbilical cord, ketanserin plus FLX (393 ± 28.25) decreased BPM compared to CON (450.17 ± 29.44; p=0.0078) and compared to FLX treatment alone (437.20 ± 17.28; p=0.0450). FLX treatment of dams during pregnancy reduces blood flow volume, heart rate, and blood flow velocity to the placenta via the uterine artery. The use of ketanserin, an inhibitor of serotonin receptor 2A/2C signaling, in combination with FLX, reduced the effects of FLX on the uterine artery. These data suggest that treatment with ketanserin could be utilized to alleviate the reproductive side effects of antidepressant usage for pregnant mothers while allowing the mother to remain on antidepressants. Future research should further investigate the effects of SSRI and ketanserin on blood flow to the fetus through the umbilical cord. Presentation: 6/2/2024

Disclosure: L.P. Agnew: None. R. Domingues: None. A. Weichmann: None. L.L. Hernandez: None. Maternal mental health is critical for both mother and infant and often antidepressant therapy outweighs the potential risks of selective serotonin reuptake inhibitor (SSRI) treatment; however, SSRI use is associated with adverse neonatal outcomes. Preliminary work in our laboratory revealed placental apoptosis in pregnant dams treated with fluoxetine (FLX) and dams genetically deficient for the serotonin transporter gene. We hypothesize that SSRIs decrease placental blood flow, causing apoptosis and organ death via signaling through the serotonin 2A/2C receptors. Pregnant female C57BL6 mice were randomized to be treated daily, via I.P. injection, from E10-17.5 with saline (CON; n=6), 2 mg/kg FLX (n=5), or 2 mg/kg ketanserin plus 2 mg/kg FLX (n=5). On E17.5, using high-resolution ultrasound imaging, we identified the uterine artery, individual umbilical cords, and placental disc blood vessels. We calculated blood pressure, blood volume, blood flow rate, and heart rate in the uterine artery, umbilical cord, and placental disc. FLX (decreased blood volume in the uterine artery compared to ketanserin plus FLX (48.42 ± 18.26, 116.54 ± 45.25; p=0.0077), and decreased average (89.38 ± 31.50) and peak (130.36 ± 39.05) blood velocity in the uterine artery compared to ketanserin plus FLX average (162.76 ± 68.46; p=0.0322) and peak (236.77 ± 92.43; p=0.0242) blood velocity. FLX decreased average (0.04 + 0.02) and peak (0.07 ± 0.04) blood pressure in the uterine artery compared to ketanserin and FLX treated animals average (0.12 ± 0.10; p=0.0634) and peak (0.25 ± 0.19; p=0.0412) blood pressure. Ketanserin plus FLX (391 ± 38.29) decreased heart rate (BPM) in the placental disc compared to untreated controls (450.67 ± 26.08; p=0.0128). In the umbilical cord, ketanserin plus FLX (393 ± 28.25) decreased BPM compared to CON (450.17 ± 29.44; p=0.0078) and compared to FLX treatment alone (437.20 ± 17.28; p=0.0450). FLX treatment of dams during pregnancy reduces blood flow volume, heart rate, and blood flow velocity to the placenta via the uterine artery. The use of ketanserin, an inhibitor of serotonin receptor 2A/2C signaling, in combination with FLX, reduced the effects of FLX on the uterine artery. These data suggest that treatment with ketanserin could be utilized to alleviate the reproductive side effects of antidepressant usage for pregnant mothers while allowing the mother to remain on antidepressants. Future research should further investigate the effects of SSRI and ketanserin on blood flow to the fetus through the umbilical cord. Presentation: 6/2/2024

Highly significant elevations in regional brain monoamine oxidase A (MAO-A) binding were recently reported during major depressive episodes (MDEs) of major depressive disorder (MDD). The relationship between MAO-A levels and selective serotonin reuptake inhibitor (SSRI) treatment, recovery, and recurrence in MDD is unknown. To determine whether brain MAO-A binding changes after SSRI treatment, whether brain MAO-A binding normalizes in subjects with MDD in recovery, and whether there is a relationship between prefrontal and anterior cingulate cortex MAO-A binding in recovery and subsequent recurrence of MDE. Case-control study. Tertiary care psychiatric hospital. Twenty-eight healthy subjects, 16 subjects with an MDE secondary to MDD, and 18 subjects with MDD in recovery underwent carbon 11-labeled harmine positron emission tomography scans. Subjects with MDE were scanned before and after 6 weeks of SSRI treatment. All were otherwise healthy, nonsmoking, and medication free. Subjects with MDD in recovery were followed up for 6 months after MAO-A binding measurement. Monoamine oxidase A V(T), an index of MAO-A density, was measured in the prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, dorsal putamen, ventral striatum, thalamus, anterior temporal cortex, midbrain, and hippocampus. Monoamine oxidase A V(T) was significantly elevated in each brain region both during MDE and after SSRI treatment as compared with healthy controls. During recovery, MAO-A V(T) was significantly elevated in each brain region; however, those who went on to recurrence had significantly higher MAO-A V(T) in the prefrontal and anterior cingulate cortex than those who did not. Elevated MAO-A binding after SSRI treatment indicates persistence of a monoamine-lowering process not present in health. This provides a strong conceptual rationale for continuing SSRI treatment during early remission. Greater MAO-A binding in the prefrontal and anterior cingulate cortex in subjects with MDD in recovery and its association with subsequent recurrence argue that deficient monoamine neuromodulation may persist into recovery and contribute to recurrence.

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed medications for patients with anxiety/depression. These patients often have problems with substance use, but it remains unclear whether the risk of substance misuse is influenced by SSRI treatment. We aimed to determine whether SSRI treatment is associated with a decreased risk of acute substance misuse-related outcomes. Cohort study following individuals through Swedish nation-wide registers between July 2005 and December 2013 and comparing the risk of substance misuse outcomes during periods on- versus off-treatment within the same individual. Swedish general population. Individuals with a newly dispensed prescription of SSRIs between July 2006 and December 2013 and an ICD-10 diagnosis of anxiety/depressive disorder before the first treatment initiation. The cohort included 146 114 individuals (60.7% women). Substance misuse outcomes included ICD-10 diagnoses of acute intoxications (F10.0-F19.0), accidental poisonings by alcohol or drugs (X41-X42, X45-X46) and substance-related criminal offenses. The absolute rate of substance misuse increased sharply before the onset of SSRI treatment and decreased after treatment initiation. Stratified Cox regression models showed an elevated risk [hazard ratio (HR)=1.70, 95% confidence interval (CI)=1.62-1.78] of substance misuse outcomes during a 1-month period preceding treatment initiation, compared with the reference period of more than 1month before treatment start. The on-treatment estimates (1-30days, HR=1.29, 95% CI=1.23-1.37; 31-120days, HR=1.30, 95% CI=1.24-1.35; and >120days, HR=1.24, 95% CI=1.18-1.30 after treatment initiation] were consistently lower than the 1-month pre-treatment estimate, but still elevated compared with the reference period. For people with anxiety/depression, the risk of substance misuse appears to be particularly elevated immediately before initiating selective serotonin reuptake inhibitor (SSRI) treatment, which may reflect the emergence or worsening of substance use problems concurrently with anxiety/depression. SSRI treatment appears to be associated with a lower risk of substance misuse compared with the 1-month period preceding treatment initiation, but causality remains uncertain.

BackgroundUsing other central nervous system (CNS) medications in combination with selective serotonin reuptake inhibitor (SSRI) treatment is common. Despite this, there is limited evidence on the impact on suicidal behavior of combining specific medications. We aim to provide evidence on signals for suicidal behavior risk when initiating CNS drugs during and outside of SSRI treatment.Materials and methodsUsing a linkage of Swedish national registers, we identified a national cohort of SSRI users aged 6–59 years residing in Sweden 2006–2013. We used a two-stage Bayesian Poisson model to estimate the incidence rate ratio (IRR) of suicidal behavior in periods up to 90 days before and after a CNS drug initiation during SSRI treatment, while accounting for multiple testing. For comparison, and to assess whether there were interactions between SSRIs and other CNS drugs, we also estimated the IRR of initiating the CNS drug without SSRI treatment.ResultsWe identified 53 common CNS drugs initiated during SSRI treatment, dispensed to 262,721 individuals. We found 20 CNS drugs with statistically significant IRRs. Of these, two showed a greater risk of suicidal behavior after versus before initiating the CNS drug (alprazolam, IRR = 1.39; flunitrazepam, IRR = 1.83). We found several novel signals of drugs that were statistically significantly associated with a reduction in the suicidal behavior risk. We did not find evidence of harmful interactions between SSRIs and the selected CNS drugs.ConclusionSeveral of the detected signals for reduced risk correspond to drugs where there is previous evidence of benefit for antidepressant augmentation (e.g., olanzapine, quetiapine, lithium, buspirone, and mirtazapine). Novel signals of reduced suicidal behavior risk, including for lamotrigine, valproic acid, risperidone, and melatonin, warrant further investigation.

Background: Prenatal depression is common, with an estimate that up to one in five pregnant women suffers from depressive symptoms. Maternal depression is associated with poor pregnancy outcomes such as preterm birth and low birth-weight. Such outcomes possibly affect offspring development. Previous studies suggest placental RNA levels of the glucocorticoid receptor are altered by maternal depression or anxiety; this stress may affect the placenta of male and female foetuses differently. However, it is unknown if the protein levels and activity of this receptor are additionally affected in women with depressive symptoms or being pharmacologically treated for depression.Methods: In this study, we investigated whether the glucocorticoid receptor (NR3C1) in the placenta is affected by maternal depression and/or selective serotonin reuptake inhibitor (SSRIs) treatment. Placentas from 45 women with singleton, term pregnancies were analysed by Western blot to determine glucocorticoid receptor levels, and by DNA-binding capacity to measure glucocorticoid receptor activation.Results: There were no differences in levels of the glucocorticoid receptor or activity between groups (control, depressive symptoms, and SSRI treatment; n = 45). Similarly, there was no difference in placental glucocorticoid receptor levels or activity dependent upon foetal sex.Conclusion: Maternal depression and SSRI treatment do not affect the glucocorticoid receptors in the placenta.

A double-blind, placebo-controlled study of edivoxetine as an adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment

BackgroundSeveral studies have now examined the effects of selective serotonin reuptake inhibitor (SSRI) treatment on brain function in a variety of anxiety disorders including obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and social anxiety disorder (social phobia) (SAD). Regional changes in cerebral perfusion following SSRI treatment have been shown for all three disorders. The orbitofrontal cortex (OFC) (OCD), caudate (OCD), medial pre-frontal/cingulate (OCD, SAD, PTSD), temporal (OCD, SAD, PTSD) and, thalamic regions (OCD, SAD) are some of those implicated. Some data also suggests that higher perfusion pre-treatment in the anterior cingulate (PTSD), OFC, caudate (OCD) and antero-lateral temporal region (SAD) predicts subsequent treatment response. This paper further examines the notion of overlap in the neurocircuitry of treatment and indeed treatment response across anxiety disorders with SSRI treatment.MethodsSingle photon emission computed tomography (SPECT) using Tc-99 m HMPAO to assess brain perfusion was performed on subjects with OCD, PTSD, and SAD before and after 8 weeks (SAD) and 12 weeks (OCD and PTSD) treatment with the SSRI citalopram. Statistical parametric mapping (SPM) was used to compare scans (pre- vs post-medication, and responders vs non-responders) in the combined group of subjects.ResultsCitalopram treatment resulted in significant deactivation (p = 0.001) for the entire group in the superior (t = 4.78) and anterior (t = 4.04) cingulate, right thalamus (t = 4.66) and left hippocampus (t = 3.96). Deactivation (p = 0.001) within the left precentral (t = 4.26), right mid-frontal (t = 4.03), right inferior frontal (t = 3.99), left prefrontal (3.81) and right precuneus (t= 3.85) was more marked in treatment responders. No pattern of baseline activation distinguished responders from non-responders to subsequent pharmacotherapy.ConclusionsAlthough each of the anxiety disorders may be mediated by different neurocircuits, there is some overlap in the functional neuro-anatomy of their response to SSRI treatment. The current data are consistent with previous work demonstrating the importance of limbic circuits in this spectrum of disorders. These play a crucial role in cognitive-affective processing, are innervated by serotonergic neurons, and changes in their activity during serotonergic pharmacotherapy seem crucial.