SSRIs and Depression clinical pharmacology case study PDF

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The risk of suicidibilty amongst adolescents, SSRIs and depression essay...

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CASE STUDY: Does the use of SSRIs increase the risk of suicidal thoughts amongst children?

https://www.frontiersin.org/articles/10.3389/fpsyt.2020.00018/full Based on these findings, the FDA issued a Black Box warning in October 2004, which was then updated in 2006 to reflect data indicating risk of antidepressant-induced suicidality in young adult patients. It states in part, that “Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders” [(10) pg. 1]. On one hand, it is also important to note that no completed suicides were recorded in these clinical trials. On the other hand, study participants were typically receiving very regular clinical attention and, in most studies, participants with active suicidality were excluded. Thus, the finding of no completed suicides may not generalize to real-world patients. Additionally, it is important to note that suicidal ideation has been found to predict future suicide attempts among adolescents. Thus, increases in suicidal ideation are themselves concerning, even if no completed suicides occurred during the trials (11–13).

Escilaproplam was approved for adolescents aged 8-18 in 2009.

SSRIs inhibit the reuptake of serotonin. As a result, the serotonin stays in the synaptic gap longer than it normally would and may repeatedly stimulate the receptors of the recipient cell. In the short run, this leads to an increase in signalling across synapses in which serotonin serves as the primary neurotransmitter. On chronic dosing, the increased occupancy of postsynaptic serotonin receptors signals the pre-synaptic neuron to synthesize and release less serotonin. Serotonin levels within the synapse drop, then rise again, ultimately leading to downregulation of post-synaptic serotonin receptors.

[157] ????? SSRIs are 20-1500 fold more selective for inhibiting serotonin over norepinephrine at their respective transporter proteins and have minimal binding affinity for other postsynaptic receptors such as adrenergic α

α , and β, histamine H , muscarinic, and dopamine D receptors. SSRIs (e.g. fluoxetine and citalopram) also do not stimulate the release of serotonin or

1, 2

1

2

norepinephrine presynaptically and have weak or no direct pharmacological action at postsynaptic serotonin receptors (e.g. 5-HT

1A

, 5-HT

2A

, and 5-HT

2c

). Therefore, the increase in

activity at the postsynaptic serotonin receptors produced by SSRIs is a result of increased concentrations of serotonin in the synaptic cleft via reuptake inhibition rather than direct binding at the postsynaptic receptor. The most common side effects associated with SSRIs are nausea, insomnia, and sexual dysfunction (Papakostas, 2008).???

Depression is associated with reduced levels of the monoamines in the brain, such as serotonin (5-HT). The selective 5-HT re-uptake inhibitors (SSRIs) are thought to restore the levels of 5-HT in the synaptic cleft by binding at the 5-HT re-uptake transporter preventing the re-uptake and subsequent degradation of 5-HT. This re-uptake blockade leads to the accumulation of 5-HT in the synaptic cleft and the concentration of 5-HT returns to within the normal range. This action of SSRIs is thought to contribute to the alleviation of the symptoms of depression. In the presence of the SSRI, small amounts of 5-HT continue to be degraded in the synaptic cleft. -

low levels of serotonin have been observed in the cerebrospinal fluid of patients diagnosed with depression. 3 As a result of this hypothesis, drugs that modulate levels of serotonin such as fluoxetine were developed. 13 if word count allows

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Fluoxetine elicits antidepressant effect by inhibiting serotonin re-uptake in the synapse by binding to the re-uptake pump on the neuronal [92] [93] membrane to increase serotonin availability and enhance neurotransmission. SSRIs inhibit the serotonin transporter (SERT) at the presynaptic axon terminal. By inhibiting SERT, an increased amount of serotonin (5-hydroxytryptamine or 5HT) remains in the synaptic cleft and can stimulate postsynaptic receptors for a more extended period.[4][5][6]

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Serotonin is normally removed from the synapse by reuptake sites on the presynapric neuron. SSRIs block the serotonin reuptake sites, allowing serotonin to remain active in the synapse longer

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and does not appreciably inhibit norepinephrine and dopamine reuptake at therapeutic doses. -

SSRIs exert action by inhibiting the reuptake of serotonin, thereby increasing serotonin activity. Unlike other classes of antidepressants, SSRIs have little effect on other neurotransmitters, such as dopamine or norepinephrine.

It does, however, delay the reuptake of serotonin, resulting in serotonin persisting longer when it is released. Large doses in rats have been shown to induce a significant increase in synaptic norepinephrine and dopamine.

[78][79][80][81]

Fluoxetine increases the concentration of circulating allopregnanolone, a potent GABAA receptor positive allosteric modulator, in the brain.

[81][84] [81]

In addition, fluoxetine has been found to act as an agonist of the σ1-receptor, with a potency greater than that of citalopram. Pharmacodynamics Fluoxetine blocks the serotonin reuptake transporter in the presynaptic terminal, which ultimately results in sustained levels of 5-hydroxytryptamine (5HT) in certain brain areas.13 However, fluoxetine binds with relatively poor affinity to 5-HT, dopaminergic, adrenergic, cholinergic, muscarinic, and histamine receptors which explains why it has a far more desirable adverse effect profile compared to earlier developed classes of antidepressants such as tricyclic antidepressants.

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SSRIs also have relatively fewer side effects compared to TCAs and MAOIs due to having fewer effects on adrenergic, cholinergic, and histaminergic receptors.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and as the name suggests, it exerts it's therapeutic effect by inhibiting the presynaptic reuptake of the neurotransmitter serotonin.2 As a result, levels of 5-hydroxytryptamine (5-HT) are increased in various parts of the brain.13 Further, fluoxetine has high affinity for 5-HT transporters, weak affinity for noradrenaline transporters and no affinity for dopamine transporters indicating that it is 5-HT selective.13

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prefrontal cortex.

The chemical structure of fluoxetine, (± )-N-methyl3-phenyl-3-[(a ,a ,a-trifluoro-p-tolyl)oxy]propylamine, as shown in Fig. 1, lacks the three-fused ring system contained in tricyclic antidepressant drugs (TCAs) such as imipramine and amitriptyline. The ptrifluoromethyl substituent on the phenoxy ring of fluoxetine is an important determinant of its potency and its specificity as a serotonin-uptake inhibitor.

2.2 Phase one preclinical studies for fluoxetine established the safety of administration on individuals suffering from depression (REF P1 ON TABLE). Subsequent phase two preclinical studies established the safety, efficacy and tolerability of fluoxetine administration on children and adolescents by the comparison with placebo; The study deemed 20 mg to be a safe and effective dosage for children and adolescents. Both drugs were administered for a period of eight weeks which was considered adequate for the evaluation of short-term efficacy of antidepressant drugs. However, a follow up on patients after a period of time may have been beneficial for long-term effects. (REF p2 on table). Phase three preclinical studies compared the efficacy of fluoxetine and citalopram in a double-blind, controlled, multicentre trial in patients with major depression over an eight-week period. The age range of the participants were between 21 and 73 years. There were a total of 314 eligible patients, 153 were allocated in the citrapolam cohort and 161 in the fluoxetine cohort. Phase two and three studies both confirmed fluoxetine to be efficacious and tolerable at 20mg daily. The withdrawal rate was low around 12% for both treatments.

Note for annotated bib: ● Patris, M., Bouchard, J.-M., Bougerol, T., Charbonnier, J.-F., Chevalier, J.-F., Clerc, G., … Petersen, H. E. H. (1996). Citalopram versus fluoxetine: a double-blind, controlled, multicentre, phase III trial in patients with unipolar major depression treated in general practice. International Clinical Psychopharmacology, 11(2), 129–136. doi:10.1097/00004850-199611020-00007 ● Citalopram versus fluoxetine: a double-blind controlled, multicentre, phase III trial in patients with unipolar major depression treated in general practice. ● The antidepressant efficacy was assessed by internationally recognized scares (the MADRS, the 17-item HAMD and the CGI). The results obtained were similar on all three scales supporting the validity of the trial outcome. Furthermore, the antidepressant efficacy observed in the present study is consistent with previously reported results. ● In addition, the two treatment groups were comparable with regard to demographic and anamnestic data. 2.3 - Back Pain showed a higher frequency with citalopram than with fluoxetine (p=0.03), whereas dry mouth and weight loss were more frequent with fluoxetine (p=0.06 and p=0.07, respectively). Anxiety was recorded in equal frequency in the two groups (8 citalopram and 9 in fluoxetine patients) - Since back pain has not been reported as a side effect of citalopram or any other SSRIs this finding may be incidental. - Although the fluoxetine cohort experienced frequent recorded adverse side effects, including nausea, insomnia, anxiety and headaches, this was lower than patients taking citalopram. However, the comparison of the two drugs showed that citalopram had an earlier onset of recovery than the fluoxetine cohort. - This study established the possible adverse event of attempted suicide, where 1.8% of the fluoxetine group had attempted suicide whilst 1.9% attempted suicide in the citalopram group. - Since backpain

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Additionally, due to adverse events 6% and 2% of patients dropped out from the citalopram and fluoxetine cohorts respectively. Dry mouth and weight loss

TRIALS Trial stage

Participants

Phase 1 (preclinic al) Twenty-two normal male volunteers, recruited from the general population and ranging in age from 21 to 50 yr, were used in these studies In addition to single-dose administration, capsules containing placebo or fluoxetine (30 mg) were administered daily for 7 days in a single-blind, crossover study to 4 normal subjects (placebo always preceding fluoxetine).

Phase 2

Ninety-six child and adolescent outpatients (aged 7-17 years) with nonpsychotic major depressive disorder were randomized (stratified for age and sex) to 20 mg of fluoxetine or placebo and seen weekly for 8 consecutive weeks. Randomization was preceded by 3 evaluation visits that included structured diagnostic interviews during 2 weeks, followed 1 week later by a 1-week, single-blind placebo run-in. 48 placebo and 48 fluoxetine

Results

info

Link

Fluoxetine, administered in single doses of 1 to 90 mg produced no behavioral or adverse effects. Similarly, after 1 wk of jiuoxetine administration, no behavioral or adverse effects were observed. There were no perceptible changes in the behavior of these subjects, nor were there any adverse side effects

Suggests it is safe and there are no adverse effects.

https://sc ihub.se/ht tps://doi. org/10.1 002/cpt1 9782344 21#

This study showed that fluoxetine is safe to prescribe for children and adolescents. Placebos were used for comparison.

https://sc ihub.do/ht tps://pub med.ncbi .nlm.nih. gov/9366 660/#

(from other paper): This is in agreement with an early safety phase I study of fluoxetine in 2 1 normal male subjects, who experienced no subjective or objective behavioral or psychologic effects while taking fluoxetine at a dose which caused 65% inhibition of 5-HT uptake in platelets (30 mg daily; total dose 2 10 mg) (249). Measurement of 5-HT uptake in platelets of human ex vivo was used as a pharmacodynamic indicator of fluoxetine potency in Phase I clinical studies ( 164) Our study was undertaken to evaluate the comparative efficacy, safety, and tolerability of fluoxetine treatment compared with placebo in child and adolescent out patients with nonpsychotic MDD. Fluoxetine was superior to placebo in the acute phase treatment of major depressive disorder in child and adolescent outpatients with severe, persistent depression. Complete remission of symptoms was rare. CONCLUSION These data indicate that fluoxetine at 20 mg/d is safe and effective in children and adolescents with MDD. Replication is needed to evaluate the certainty of this finding. In addition, whether long-term treatment would result in the amelioration of school, general functioning, or concurrent comorbidities is unknown. How long to con¬ tinue fluoxetine treatment, assuming it is effective, de¬ serves study. Subsequent analyses to evaluate predictors of response are planned.

Phase 3 - 1996.

Citalopram versus fluoxetine: a double-blind controlled, multicentre, phase III trial in patients with unipolar major depression treated in general practice. eight weeks.

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The frequency of adverse effects were generally low in the fluoxetine group. nausea , insomnia, anxiety and headaches were the most frequently recorded adverse effects in F. Three patients attempted suicide. At phase 3 F was found to be effectious at 20 mg daily. The results of this study demonstrated that citalopram and fluoxetine were both effective at a dose of 20mg daily and that they were equally effective, in the treatment of patients with unipolar major depression in general practice. Both C and F were considered to be well tolerated. C showed an earlier onset of recovery than F.

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Postmarkete d

Phase 3

Trial method: After a 3-week screening period, 122 children and 97 adolescents with MDD ( DSM-IV) were randomly assigned to placebo or fluoxetine. After a 1-week placebo lead-in, fluoxetine-treated patients received fluoxetine 10 mg/day for 1 week, then fluoxetine 20 mg/day for 8 weeks.

463 participants (only 117 were given fluoxetine)

Conclusion: Fluoxetine 20 mg daily appears to be well tolerated and effective for acute treatment of MDD in child and adolescent outpatients. Fluoxetine is the only antidepressant that has demonstrated efficacy in two placebo-controlled, randomized clinical trials of pediatric depression. Fluoxetine was associated with greater mean improvement in Children's Depression Rating Scale-Revised (CDRS-R) score than placebo after 1 week ( p < .05) and throughout the study period. Significantly more fluoxetine-treated patients (41%) met the prospectively defined criteria for remission than did placebo-treated patients (20%) ( p < .01). More fluoxetine- (65%) than placebo-treated (53%) patients met the prospectively defined response criterion of ≥30% decrease in CDRS-R score, but this difference was not significant ( p = .093). Significantly more fluoxetine-than placebo-treated patients completed acute treatment ( p = .001). There were no significant differences between treatment groups in discontinuations due to adverse events ( p = .408).

Suggesting the safety and tolerability of the drug. 1.8% commited suicide. Compared to 350 million people taking the drug. 630 thousand people may attempt suicide. Therefore, the package inserts are necessary. States that from 314 patients (153 in C group and 161 in F group), there were 3 attempted suicide cases in each group (1.9% and 1.8%) ● ●

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Recent trial Confirming the ABOVE phase three trial with the 20 mg recommended dosage. As they compared with placebo

In this trial fluoxetine was used as an active comparator

https://sc ihub.se/1 0.1097/0 0004850 1996110 2000007#

https://pu bmed.nc bi.nlm.ni h.gov/12 364842/ https://ja acap.org/ article/S0 8908567(09) 607656/fulltext

https://cli nicaltrials .gov/ct2/

Randomised allocation 2009 to 2011 Quadruple masking (participant, care provider, investigator, outcome assessor.

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A double-blind, efficacy and safety study of duloxetine versus placebo in the treatment of children and adolescents with major depressive disorder.

During the acute treatment phase of the trial there were only 3 individuals with suicidal ideation, two of which were in the fluoxetine cohort.

20 milligram (mg) orally, once daily for 10 weeks (acute treatment phase) and 20-40 mg orally, once daily for additional 6 months (extension phase)

Phase 3

A Study of Fluoxetine in Major Depressive Disorder (MDD) Short-Term Dosing 513 participants Randomized Trial was 6 weeks Triple (Participant, Investigator, Outcomes Assessor)

168 participants were in the 20 mg group, 83 were in the 40 mg group and 259 were in the placebo group were analysed for suicidal ideation 5 in the 20 mg group, 6 in the 40mg fluoxetine group and 8 in the placebo group. 3.08% experienced suicidal ideation in the placebo group 7.2% experienced suicidal ideation in the 40 mg fluoxetine group 2.9% experience suicidal ideation in the 20 mg fluoxetine group

A Phase 3, Randomized, Placebo-Controlled, Double-Blind, Parallel-Design Study to Evaluate the Short-Term, Fixed Dose Efficacy and Safety of LY110140 Once Daily Dosing in Japanese Patients With Major Depressive Disorder. experimental : 20 mg fluoxetine (capsules) administered orally, once daily, for 6 weeks 40 mg fluoxetine (capsules) administered orally, once daily, for 6 weeks. Placebo (capsules) administered orally, once daily, for 6 weeks

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This suggests that participants on higher doses of fluoxetine are more likely to experience adverse effects of suicidal ideation. Although lower dosages at 20 mg per day shows similar results to the placebo suggesting that the administration of fluoxetine at 20 mg is safe.

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This trial investigated the outcome of fluoxetine by comparing 20 mg of fluoxetine to 40 mg and a placebo group. Although in the trial the number of suicidal ideation in both fluoxetine groups was slightly lower than the placebo group however the number of participants must be taken into account. Placebo has a higher number of participants

https://www.nejm.org/doi/10.1056/NEJMp1408480?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub+

show/res ults/NCT 0084969 3? term=fluo xetine&r ecrs=e&c ond=Dep ression& age=0&p hase=2& draw=2& rank=7

https://cli nicaltrials .gov/ct2/ show/res ults/NCT 0180861 2

+0pubmed# https://sci-hub.do/https://doi.org/10.1517/17460441.2014.907790 -

Thus, an SSRI was developed by Eli Lilly and Company, the compound numbered LY110140 (fluoxetine) was initially approved as a drug for medical use in Belgium in 1986, although it was not approved by the FDA until 1987, under the name of Prozac. Numerous clinical trials reported that the antidepressant efficacy of fluoxetine was as potent as the TCA but with fewer side effects due to its selective profile [3]. However, some adverse effects are associated with fluoxetine, which could limit the treatment adherence, and not all patients reached the desired therapeutic response after fluoxetine treatment. However, this antidepressant drug was a breakthrough in the treatment of depression, ...