SSRI Therapy Research Articles

A randomized controlled add-on trial of fluoxetine and cognitive behavioral therapy for help-seeking men with a sexual interest in children: presentation of the PARACHUTES trial protocol and initial feasibility data.

Sexual Interest in Children (SIC) is a major risk factor for sexual offending, yet clinical trials are sparse. The present protocol outlines a randomized controlled trial (RCT) that aims to investigate the effectiveness of fluoxetine and Cognitive Behavioral Therapy (CBT) in help-seeking men with SIC. Adult men contacting the Swedish telephone helpline PrevenTell are screened for inclusion and invited to further assessment on site. One hundred and eleven men with SIC (defined as DSM-5 pedophilic disorder or hebephilia) will be randomized (1:1:1 ratio) to receive one of three interventions for 14 weeks: (1) an internet-administered psychoeducational program (iPP), (2) iPP and the addition of fluoxetine 20-40 mg or (3) iPP and the addition of internet-administered CBT (iCBT). Exclusion criteria include severe psychiatric illness, contraindicating treatment and an elevated risk of committing hands-on sexual offences. Symptom intensity is assessed at baseline, pre-treatment, every other week for 12 weeks, and post treatment. The primary outcome measure is the Sexual Interest in Children: Current Assessment Scale (SIC: CAS) that quantifies sexual behaviors associated with SIC as well as perceived distress and impairment. Secondary outcomes include measures of dynamic risk-factors for committing sexual offences. The data collected during the initial 20 months of recruitment were analyzed to predict the required number of individuals to be screened and estimate the probable length of the data collection phase. As of March 2022 to November 2023, 146 men have called PrevenTell and disclosed a sexual interest in minors. Following pre-screening, 110 men were excluded from participation in the trial. Current SSRI therapy was the primary reason for exclusion (n = 24; 22%), followed by an elevated risk of committing hands-on sexual offences (n = 14; 13%). Among the 31 men who underwent the screening procedure on site, 26 were allocated to either iPP, iPP+fluoxetine, or iPP+iCBT. The recruitment rate indicates that the trial will be concluded within the pre-estimated timeframe. This is the first RCT of treatment with SSRI and iCBT in a population of help-seeking men with SIC. The significance of this trial and its methodological strengths and limitations are discussed.

Does SSRI therapy improve quality of life in adults with IBS?

Gagnon, Dominique G. MD, PhD1; Foy, Robert E. DO1; Hannabas, Greg P. MD, MPH, MPA1; Haynes, Jamie MD1; Babb, Franklyn2 Author Information

COPD and Depression Analysis in Regard to Obstructive Pulmonary Levels.

Depression symptoms take place recurrently in patients suffering from COPD. This study aims to assess the effects of antidepressant therapy in patients with COPD and a depressive disorder in relation to COPD levels. The study population consisted of N = 87 patients diagnosed with COPD, according to the GOLD criteria, and a depressive disorder. All of the patients were subjected to clinical and psychiatric exploration according to psychiatric assessment instruments, which was followed by SSRI therapy for the duration of 8 weeks. The main methods used were descriptive statistics and analysis of variance. The results showed a different distribution of depressive symptoms at a different stage of COPD by FEV1 (χ2 = 30.47, df = 6, p < 0.01) and by mMRC (χ2 = 34.6, df = 6, p < 0.01). After the application of SSRIs, there was a significant improvement in HDRS scores in all stages of COPD by FEV1 (χ2 = 251.62, df = 9, p < 0.01) and by mMRC (χ2 = 919.17, df = 9, p < 0.01). This study contributes to the improvement in the quality of life of patients by the targeted application of SSRI therapy and, therefore, more precise and better overall treatment results.

Апатия у пациентов с депрессией, получающих терапию СИОЗС

Апатия у пациентов с депрессией, получающих терапию СИОЗС

Optimization of treatment of depression with administration of ethylmethylhydroxypyridine succinate (Mexicor)

To investigate the therapeutic efficacy and tolerability of Mexicor as an adjuvant in the treatment of depression with SSRI antidepressants. The study included 100 patients, aged 18-50 years, with verified depression of mild (n=32) or moderate (n=68) severity. Patients (n=50) of the main group, along with basic antidepressant therapy with SSRIs, received Mexicor at a dose of 600 mg/day, in the comparison group (n=50) - only SSRIs. Clinical-psychopathological, psychometric, using the HDRS-21 scale, CGI, HADS, fluency test of speech responses and the Stroop test, statistical research methods were used. The reduction of depressive symptoms on the HDRS-21 scale, starting from the fourth week, was statistically significantly superior to that in the comparison group (p<0.001), the reduction in the severity of the condition on the CGI scale in the main group was also significantly greater than in the comparison group (17.3% and 9.6% respectively, p<0.05). A significant improvement in speech fluency was found in the main group (p<0.05). Adverse events in the main group were significantly less common (p<0.001). Administration of Mexicor together with SSRIs leads to improved efficacy and tolerability of antidepressant therapy, and in the future, Mexicor may be recommended as an adjuvant in SSRI therapy for depression.

Mechanisms of SSRI Therapy and Discontinuation.

SSRIs are one of the most widely used drug therapies in primary care and psychiatry, and central to the management of the most common mental health problems in today's society. Despite this, SSRIs suffer from a slow onset of therapeutic effect and relatively poor efficacy as well as adverse effects, with recent concerns beingfocused on a disabling SSRI discontinuation syndrome. The mechanism underpinning their therapeutic effect has long shifted away from thinking that SSRIs act simply by increasing 5-HT in the synapse. Rather, a current popular view is that increased 5-HT is just the beginning of a series of complex downstream signalling events, which trigger changes in neural plasticity at the functional and structural level. These changes in plasticity are then thought to interact with neuropsychological processes to enhance re-learning of emotional experiences that ultimately brings about changes in mood. This compelling view of SSRI action is underpinning attempts to understand fast-acting antidepressants, such as ketamine and psychedelic drugs, and aid the development of future therapies. An important gap in the theory is evidence that changes in plasticity are causally linked to relevant behavioural effects. Also, predictions that the SSRI-induced neural plasticity might have applicability in other areas of medicine have not yet been borne out. In contrast to the sophisticated view of the antidepressant action of SSRIs, the mechanism underpinning SSRI discontinuation is little explored. Nevertheless, evidence of rebound increases in 5-HT neuron excitability immediately on cessation of SSRI treatment provide a starting point for future investigation. Indeed, this evidence allows formulation of a mechanistic explanation of SSRI discontinuation which draws on parallels with the withdrawal states of other psychotropic drugs.

Moving beyond first-line treatment options for OCD.

OCD is characterized by obsessions and compulsions that cause distress, are time-consuming, and interfere with a patient's social, occupational, or other areas of functioning. SSRIs are first-line pharmacologic treatment options and produce response rates of up to 60% in patients with OCD. Several potential strategies have been evaluated for enhancing patient response, including high-dose SSRI therapy, antipsychotic augmentation, and memantine augmentation. Three patient cases are used to explore treatment guidelines, evaluate existing literature, and provide pharmacotherapy recommendations for the management of patients with OCD when first-line therapy fails.

SSRI-associated apathy in Alzheimer's disease: a case series

Apathy is one of the most common manifestations of neurodegenerative pathology, including Alzheimer's disease (AD). Despite such a significant role of apathy in the course of the disease, there are no unambiguous recommendations for the treatment and prevention of this symptom complex. Some classes of psychotropic drugs commonly prescribed for AD, such as antidepressants of the SSRI class, may themselves cause apathy. The authors present a series of clinical observations describing four cases of deterioration in the condition of patients with AD during SSRI therapy. The features of the clinical course of the disease are discussed, new strategies for drug therapy are proposed.

Quetiapine Add-On Therapy May Improve Persistent Sleep Disturbances in Patients with PTSD on Stabile Combined SSRI and Benzodiazepine Combination: A One-Group Pretest-Posttest Study.

To assess potential benefits of quetiapine for persistent sleep disturbances in patients with posttraumatic stress disorder (PTSD) on stable combined SSRI and benzodiazepine therapy, who previously failed to respond to various benzodiazepine and non-benzodiazepine hypnotic adjuvant treatment as well as to first-generation antipsychotic add-on treatment. Fifty-two male PTSD outpatients on stable combination treatment with SSRI and benzodiazepines, with persistent sleep disturbances not responding to prescription of zolpidem, flurazepam, nitrazepam, promazine, and levopromazine, were assessed for sleep disturbances improvements after prescription of quetiapine in the evening. Each patient met both ICD-10 and DSM-IV criteria for PTSD. Psychiatric comorbidity and premorbidity were excluded using the Mini-International Neuropsychiatric Interview (MINI). Improvement on the CAPS recurrent distressing dream item, reduction in the amount of time needed to fall asleep, prolongation of sleep duration, and reduction in average number of arousals per night in the last 7 days before the assessment period were used as efficacy measures. All sleep-related parameters improved significantly at the end of a five-week follow-up: sleep duration increased by one hour (p<0.001), sleep latency decreased by 52.5 minutes (p<0.001), median number of arousals per night decreased from two to one (p<0.001), CAPS recurrent distressing dream item median decreased from five to four (p<0.001), and the number of patients dissatisfied with their sleep quality and quantity decreased from 45 to two (p<0.001). Quetiapine prescribed in the evening may be successful therapy for persistent sleep disturbances in patients with PTSD and generally good response to an SSRI and benzodiazepine combination, who previously failed to respond to some of the usual hypnotic medication or addition of first-generation antipsychotics: zolpidem, flurazepam, nitrazepam, promazine, and levopromazine.

Hyperinsulinemia Associated Depression.

Hyperinsulinemia promotes fat accumulation, causing obesity. Being an inflammatory state, obesity can induce further inflammation and is a risk factor for HPA (hypothalamic pituitary axis) dysregulation through hypercortisolism-related hyperglycemia. In another hypothesis, the sympathetic nervous system (SNS) plays a significant role in the regulation of hormone secretion from the pancreas such as an increase in catecholamines and glucagon as well as a decrease in plasma insulin levels, a disruption on SNS activity increases insulin levels, and induces glycogenolysis in the liver and lipolysis in adipose tissue during hypoglycemia. Hyperglycemia-hyperinsulinemia exacerbates inflammation and increases the oxidative stress along with regulating the levels of norepinephrine in the brain sympathetic system. Increased inflammatory cytokines have also been shown to disrupt neurotransmitter metabolism and synaptic plasticity which play a role in the development of depression via inhibiting serotonin, dopamine, melatonin, and glutamate signaling. An increased level of plasma insulin over time in the absence of exercising causes accumulation of lipid droplets in hepatocytes and striated muscles thus preventing the movement of glucose transporters shown to result in an increase in insulin resistance due to obesity and further culminates into depression. Further hyperinsulinemia-hyperglycemia condition arising due to exogenous insulin supplementation for diabetes management may also lead to physiological hyperinsulinemia associated depression. Triple therapy with SSRI, bupropion, and cognitive behavioral therapy aids in improving glycemic control, lowering fasting blood glucose, decreasing the chances of relapse, as well as decreasing cortisol levels to improve cognition and the underlying depression. Restoring the gut microbiota has also been shown to restore insulin sensitivity and reduce anxiety and depression symptoms in patients.

Sexual dysfunction in patients with MDD treated with SSRIs - causes, measurement and prevention

Major Depressive Disorder(MDD) is serious psychiatric condition and they affect one in five people during their lifetime, the annual prevalence rates for the US population are 7.1% among adults, slightly more common among women (8.7%) than men (5.3%). Selective serotonin reuptake inhibitors are among the pharmacological agents most commonly used in the treatment of MDD.&#x0D; The mechanism of action of antidepressants is not yet fully understood. Currently, it is believed that the mechanism of the so-called down-regulation, i.e. reducing the density of receptors in the postsynaptic membrane, in this case mainly 5HT2 receptors. All of the antidepressants in use today have some common side effects. The side effect that will be discussed in the broadest possible way in this paper are sexual dysfunctions appearing during the therapy. Measuring the degree to which a given substance affects the sexual function of a patient diagnosed with MDD encounters many difficulties on its way. There are currently several questionnaires enabling such an assessment, the most common are CSFQ, ASEX and SexFX. Also the major problem is Post SSRI Sexual Disfunction. A number of animal studies have proven that prolonged exposure to SSRIs leave permanent changes in the CNS, but unfortunately, similar studies have not yet been conducted in humans. The aim of this study is to present the problem of sexual dysfunction as a side effect of SSRI therapy, to present the causes and to propose a strategy to combat SSRI-induced sexual dysfunctions.

Among people with anxiety, what is the effective duration of SSRI therapy to prevent relapse?

Among people with anxiety, what is the effective duration of SSRI therapy to prevent relapse?

Graph theoretical measures of the uncinate fasciculus subnetwork as predictors and correlates of treatment response in a transdiagnostic psychiatric cohort

The internalizing psychopathologies (IP) are a highly prevalent group of disorders for which little data exists to guide treatment selection. We examine whether graph theoretical metrics from white matter connectomes may serve as biomarkers of disease and predictors of treatment response. We focus on the uncinate fasciculus subnetwork, which has been previously implicated in these disorders. We compared baseline graph measures from a transdiagnostic IP cohort with controls. Patients were randomized to either SSRI or cognitive behavioral therapy and we determined if graph theory metrics change following treatment, and whether these changes correlated with treatment response. Lastly, we investigated whether baseline metrics correlated with treatment response. Several baseline nodal graph metrics differed at baseline. Of note, right amygdala betweenness centrality was increased in patients relative to controls. In addition, white matter integrity of the uncinate fasciculus was decreased at baseline in patients versus controls. The SSRI and CBT cohorts had increased left frontal superior orbital betweenness centrality and left frontal medial orbital clustering coefficient, respectively, suggesting the presence of treatment specific neural correlates of treatment response. This study provides insight on shared white matter network features of IPs and elucidates potential biomarkers of treatment response that may be modality-specific.

Response to SSRI intervention and amygdala activity during self-referential processing in major depressive disorder

There are conflicting reports on the impact of antidepressants on neural reactions for positive information. We thus hypothesized that there would be clinically important individual differences in neural reactivity to positive information during SSRI therapy. We further predicted that only those who responded to SSRIs would show increased amygdala reactivity to positive information following treatment to a level similar to that seen in healthy participants. Depressed individuals (n = 17) underwent fMRI during performance of a task involving rating the self-relevance of emotionally positive and negative cue words before and after receiving 12 weeks of SSRI therapy. At post-treatment, SSRI responders (n = 11) had increased amygdala activity in response to positive stimuli, and decreased activity in response to negative stimuli, compared to non-responders (n = 6). Results suggest that normalizing amygdala responses to salient information is a correlate of SSRI efficacy. Second line interventions that modulate amygdala activity, such as fMRI neurofeedback, may be beneficial in those who do not respond to SSRI medications.

Systemic Solutions for Addressing Early Recognition and Treatment of Antenatal and Postpartum/Postnatal Depression in Psychiatry Clinic in Skopje, North Macedonia

Background: It is considered that depressive disorder most often begins in the reproductive period, around 20 years of age. Introduction: The greatest risk or danger for the young depressed mother is suicide, which is being considered the second cause of death in the young during the reproductive years. Unfortunately, it happens usually at the end of the pregnancy or during the first postpartum year. Materials and methods: The investigation comprised 69 patients at the age between 18 and 44 years, with postpartum depression. Patients were diagnosed and treated during their pregnancy and postpartum period. Patients were analyzed by using a structured clinically diagnostic psychiatric interview, psychodiagnostic instruments for assessment of anxiety and depression, HAM-A and HAM-D. Depression and anxiety were evaluated in the beginning of the treatment and after three months of treatment. Patients were treated with psychological interventions and pharmacological treatment, SSRI or SNRI antidepressant therapy, during pregnancy or postpartum period. Results: Cross-sectional study was conducted in a 3-month-period and comprised 69 patients, of which 71.0% were at the age older than 30 years, and 29.0% younger than 30 years. Of these, 81.5% of patients received antidepressants, 24.6% received antipsychotics and anxiolytics, alone or in combination. Discussion: The results have shown a statistically significant presence of risk factors in patients with antenatal or postpartum depression. The results have shown a significant reduction of anxiety and depression after application of SSRI therapy and psychological individual and group interventions by empowering the mother to care for herself and her child. Conclusion: Proper care for the mental health of the mother is the care for the entire society, healthy mother, healthy children and healthy society. Early recognition of the risk factors for development of antenatal depression leads to prevention of onset of antenatal or postpartum depression.

Antiplatelet effects of citalopram in patients with ischaemic stroke: A randomized, placebo-controlled, double-blind study

We evaluated the effect of SSRI treatment on platelet aggregation in patients with ischaemic stroke and included patients from the randomized double-blind controlled study of citalopram in acute ischaemic stroke (TALOS). Patients on clopidogrel were included 6 months after acute ischaemic stroke. Platelet parameters, including P2Y12 platelet reactivity using the VerifyNow System, were measured at the last day of study treatment and repeated after a 14-day wash-out period. A total of 60 patients were included (n = 32 randomized to citalopram). Platelet aggregation levels did not differ between the citalopram group (mean 116, 95% CI 89 to 143) and the placebo group (mean 136, 95% CI 109 to 163) (On-treatment, p = 0.14). Similarly, there was no significant change in platelet aggregation in the citalopram group from on-treatment to post-treatment (mean difference 2.0; 95% CI −18 to 14). Platelet count, size and turnover were not affected by SSRI treatment. In conclusion, SSRI therapy did not lead to statistically significant inhibition of platelet aggregation in ischaemic stroke patients treated with clopidogrel.

Superior Outcome in Elderly AML Patients Receiving Adjuvant Serotonin-Reuptake-Inhibitors during Induction

Background: Acute myelogenous leukemia [AML] in elderly patients has a poor prognosis. Age is a unique adverse predictor. However, the higher incidence of complex karyotype, secondary AML, and other unfavorable European-Leukemia-Network -2017 [ELN-2017] features are common. Induction failure is frequent and associated with chemotherapy resistance. These factors highlight an urgent need for "novel" therapy development. In recent years, in vitro, anti-tumor activity of Selective Serotonin Reuptake Inhibitors [SSRIs], such as Sertraline, have been demonstrated. Increased apoptosis, autophagy activation, and favorable modulation of P-glycoprotein and multidrug-resistance-associated-proteins are proposed mechanisms of anti-tumor effect. In this study, our primary aim was to detect "early [day 14] blast reduction" among patients [pt] receiving adjuvant SSRIs in combination with induction therapy as compared to patients who do not receive SSRIs. Additionally, we evaluated overall survival [OS] and relapse free survival [RFS] patients with and without exposure to SSRIs. Methods: With prior IRB approval, 176 pt diagnosed with AML from 1995 to 2017 at Baylor College of Medicine institutions [Michael E. DeBakey VA Medical Center and Baylor St. Luke's Medical Center] were analyzed. We identified older (age&amp;gt;65) pts who received or did not receive SSRI for at least 6 months prior to induction therapy. "Early blast reduction" was evaluated by bone marrow (BM) exam on day 14. OS and RFS were evaluated by the Kaplan Meier method using PRISM 5. Independent variables with potential effect on OS and RFS [Mann-Whitney P=&amp;lt;0.05] were incorporated into a Cox proportional regression model to estimate the independent predictive SSRI exposure's effect on both time to event variables. Statistical analysis was performed with SAS software, NC, USA and GraphPad Prism 5. Results: Among our AML cohort, 93/177 (52.8%) AML pt were older than 65 y. Median age was 72.1 y (67-82). 78/93 (83.8 %) pts had available data for response, survival and relapse evaluation after induction therapy. 12/78 pt (15.4%) and 66/78 pt (84.6%) received or not received SSRIs, respectively. Baseline characteristics were balanced among AML pt exposed or not to SSRI and are depicted in table 1. Post-induction, day 14 residual blast among those SSRI pos vs SSRI neg was 1.17% vs 19.9%, p=0.005. Median OS and RFS among AML pt older than 65 y exposed or not exposed to SSRIs were 368 d vs 90 d, p=0.005 [HR=2.2; 95% CI 1.2-3.9] and 515 d vs 83 d, p=0.01 [HR= 1.2;95% CI 1.4-29.09] [Fig.1Aand B]. A cox multivariate model adjusting for potential confounders that included ELN-2017 classification, absolute monocyte count at diagnosis, body mass index demonstrated that SSRI therapy [p=0.007, HR=0.78; 95% CI 0.65- 0.93] and ELN-2017 classification [p=0.005, HR= 1.16; 95% CI 1.04-1.29] were the only independent predictors for survival. A similar analysis was performed to evaluate the independent effect of SSRI exposure on RFS after adjusting for potential bias. This showed that SSRI therapy [p= 0.02, HR=0.72; 95% CI 0.55-0.95] and ELN-2017 [p=0.03, HR=1.18; 95% CI 1.01-1.38] retained prediction for relapse risk. Conclusions: Our study demonstrates improved OS and RFS among AML pt older than 65 y who were exposed to SSRIs. This is the first demonstration of the activity of SSRI in AML. At day 14, a lower number of blasts in pt exposed to SSRIs suggests that these drugs facilitate blast eradication when combined with induction therapy. We observed a 22% lower risk of death and 28% lower probability of relapse among AML pt &amp;gt;65 y receiving induction who were exposed to SSRI. Our preliminary data supports the feasibility of combining adjuvant SSRIs with induction therapy for the treatment of elderly AML pt. Disclosures No relevant conflicts of interest to declare.

Brain interlukin33 protects neurons from oxidative attack: A potential therapeutic target for Bipolar Disorder

Selective serotonin (norepinephrine) reuptake inhibitors (SS(N)RIs) are used in the treatment of depression. The aim of this study was to assess the persistence with SS(N)RIs in outpatients treated by general practitioners (GP) or psychiatrists (PSY) in Germany, and to investigate the association between persistence and the following factors: age, gender, specialty of the physician initiating treatment, initial molecule, and prior antidepressant prescription.A longitudinal pharmacy database (IMS LRx®) was used to identify patients (>18 years old) who had received an initial prescription (Rx) of an SS(N)RI between January 2014 and December 2016 (index date) from a GP or a PSY. Patients were only included if they had at least one year of pre-index observation time. The primary outcome was the rate of patients without SS(N)RI treatment discontinuation in the 12 months following the index date. Persistence was assessed using the Kaplan-Meier method. Cox regression was used to determine the impact of covariates on persistence.A total of 1,213,344 patients were eligible to be included (mean age: 55.9 years, 67% women). Twelve months after initiation of SS(N)RI therapy, 28.3% of patients were persistent. Higher age was significantly associated with a lower discontinuation risk. In addition, female gender, treatment initiation by a PSY, and treatment with other antidepressants at the index date were associated with a slightly higher persistence. There were significant associations for the different molecules; however, the absolute differences were small (below 5%).The results show that the proportion of patients receiving long-term SS(N)RI therapy (at least 12 months) was low. Discontinuation depended mainly on age and, to a lesser degree, on gender, the specialty of the physician initiating treatment, other antidepressant prescription at the index date, and initial molecule.

Association of Upper GI Bleed in Patients with Budesonide and SSRI Therapy in Chrons Disease: A Comparative Clinical Study

Association of Upper GI Bleed in Patients with Budesonide and SSRI Therapy in Chrons Disease: A Comparative Clinical Study

Persistence with selective serotonin (norepinephrine) reuptake inhibitors in Germany—A retrospective database analysis

IntroductionSelective serotonin (norepinephrine) reuptake inhibitors (SS(N)RIs) are used in the treatment of depression. The aim of this study was to assess the persistence with SS(N)RIs in outpatients treated by general practitioners (GP) or psychiatrists (PSY) in Germany, and to investigate the association between persistence and the following factors: age, gender, specialty of the physician initiating treatment, initial molecule, and prior antidepressant prescription. MethodologyA longitudinal pharmacy database (IMS LRx®) was used to identify patients (>18 years old) who had received an initial prescription (Rx) of an SS(N)RI between January 2014 and December 2016 (index date) from a GP or a PSY. Patients were only included if they had at least one year of pre-index observation time. The primary outcome was the rate of patients without SS(N)RI treatment discontinuation in the 12 months following the index date. Persistence was assessed using the Kaplan-Meier method. Cox regression was used to determine the impact of covariates on persistence. ResultsA total of 1,213,344 patients were eligible to be included (mean age: 55.9 years, 67% women). Twelve months after initiation of SS(N)RI therapy, 28.3% of patients were persistent. Higher age was significantly associated with a lower discontinuation risk. In addition, female gender, treatment initiation by a PSY, and treatment with other antidepressants at the index date were associated with a slightly higher persistence. There were significant associations for the different molecules; however, the absolute differences were small (below 5%). ConclusionThe results show that the proportion of patients receiving long-term SS(N)RI therapy (at least 12 months) was low. Discontinuation depended mainly on age and, to a lesser degree, on gender, the specialty of the physician initiating treatment, other antidepressant prescription at the index date, and initial molecule.