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TEMPLATE DESIGN © 2008 www.PosterPresentations.com Treating Depression with St. John’s Wort: Therapeutic Breakthrough or Hidden Hazard? Elisa Bailey, Alissa Basehoar, Jeannie Kim, Rozine Lindamood, Lauren Pearson, Justin Siegfried, Tiffany VanDervort Class of 2013 – School of Pharmacy – Virginia Commonwealth University Abstract Introduction Pharmacokinetics/Pharmacodynamics Hyperforin is the only compound listed that has been shown to cross the blood brain barrier in animal studies. Hyperforin is believed to be responsible for St. John’s Wort’s ability to non-selectively block neurotransmitter reuptake. It is also believed to be responsible for the many drug-drug interactions because it activates human pregnane X receptor, leading to increased drug metabolism by cytochrome P450 3A4. Hyperforin was also shown to increase the activity of CYP 1A2 and 2C9. There is also limited evidence that hyperforin induces the P-glycoprotein efflux transporter. The two napthodiantrones present in St. John’s Wort are hypericin and pseudohypericin. Both of these compounds have low bioavailability due to their low water solubility. Hypericin treatment led to decreased plasma levels of adrenocorticotropic hormone and cortisol. High doses of hypericin can cause photosensitization to UV light, called hypericism. The main flavonoids found in hypericum perforatum are the monoglycosides: quercitrin, isoquercitin, and hyperoside; and the diglycoside rutin. The flavonoids undergo extensive Phase II metabolism in the intestinal wall releasing the aglycoside, quercetin. Quercetin exhibits a double peak plasma profile with the first peak appearing after 1.5 hours and the second, lower peak, after 9 hours. Studies show that flavonoids present in St. John’s Wort weakly inhibit monoamine oxidase. Treating Depression with St. John’s Wort Pharmacology/Mechanism of Action Although St. John’s Wort contains at least seven constituents that may contribute to its pharmacological effects, hypericin and hyperforin are the major active constituents responsible for antidepressant effect. Research initially focused on hypericin as the active component of St John's Wort exerting the herb's antidepressant effects. Early studies showed that St. John’s Wort inhibits monoamine oxidase-A (MAO-A) and MAO-B activity in rat brain mitochondria in vitro. Receptor binding and enzyme inhibition assays demonstrated significant receptor affinity of St. John’s Wort for adenosine, GABA A , GABA B , benzodiazepine and MAO- A,-B. It inhibits the uptake of serotonin (5- hydroxytrptamine; 5-HT), dopamine, and norepinephrine with approximately equal affinity and also shows a down- regulation of beta receptors and an up- regulation of 5- HT 2 receptors in rat frontal cortex. Hyperforin has now emerged as one of the major active constituents in St. John’s Wort’s antidepressive effects. Hyperforin has been shown to be an uptake inhibitor of 5-hydroxytryptamine, dopamine, noradrenaline (norepinephrine), GABA and l-glutamate in preparations and to inhibit 5-HTuptake in rat peritoneal cells in a dose-dependent manner. Studies have reported that the mechanism of action of hyperforin in serotonin uptake inhibition appears to be associated with an increase of free intracellular sodium ion concentrations and that this may be secondary to activation of Na + /H + exchange as a result of a decrease in intracellular pH. Further in vitro experiments have demonstrated hyperforin does increase both intracellular sodium ion and calcium ion concentrations, and this is mediated Drug-Drug Interactions Toxicity/Side Effects A systematic review of current evidence concluded that Hypericum perforatum extracts are well tolerated and safe, aside from the potential for interactions with other drugs. St. John's Wort was associated with fewer and milder adverse reactions when compared with conventional antidepressants. The commonly experienced side effects are listed below: Conclusions References •Dry mouth •Nausea •Change in bowel habits •Itching •Photosensitization •Fatigue • Dizziness • Jitteriness • Insomnia • Sleep disorders • Headache • Induction of mania Drug Class Specific Example Metabolis m (major) Effect of interaction on drug HIV protease inhibitor Indinavi r CYP3A4 Reduction of AUC of indinavir by a mean of 57%. Reduction in exposure could lead to development of drug resistance and treatment failure in HIV patients Anticoagulan t Warfarin CYP2C9 Reduced anticoagulant effects. Monitor INR values. May need to adjust dosages of anticoagulants. Immunosuppre ssant Cyclospo rin P- glycoprot ein, CYP3A4 Subtherapeutic blood concentrations resulting in risk of rejection of the transplanted organ. May need to adjust dosages of immunosuppressant. SSRIs N/A CYP2C9 Risk of serotonin syndrome (confusion, agitation, shivering, tremor, nausea, diarrhea, lack of coordination, fever, rhabdomyolysis). Discontinue SJW. Theophylline N/A CYP 3A4, Reduced blood concentrations. Caution Compound Lag time (hrs) t max (hrs) t 1/2 (hrs) Steady State (days) Hyperforin 1 3 – 3.5 9 NR Hypericin 2 6 33 6 – 7 Pseudohyper icin < ½ 3 21 4 Monoglycosi des NR < 1 NR NR Rutin NR 7 NR NR 1) Baruch Y. Hypericum extract for treatment of depression: what's new?. Harefuah 2009;148(3):183- 185,209-210. 2) Candy B, Jones L, Williams R, Tookman A, King. Psychostimulants for depression. Cochrane Database of Systemic Reviews 2008;2:3-32. 3) Delgado PL. Depression: the case for monoamine deficiency: Journal of Clinical Psychiatry 2000:61:7- 11. 4) Kirsh I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration: PloS Medicine 2008:5:260-8. 5) Linde K, Berner MM, Kriston L. St John's Wort for Major Depression (Review). Cochrane Database of Systematic Reviews 2008;4. 6) Butterweck V. Mechanism of Action of St John's Wort in Depression: What is Known?. CNS Drugs 2003; 17(8):539-562. 7) National Institute for Clinical Excellence. Depression: management of depression in primary and secondary care. Clinical practice guideline No. 23. London: National Institute for Clinical Excellence, 2004. 8) Piscitelli S, Burstein A, Chaitt D, Alfaro R, Falloon J. Indinavir Concentrations and St John’s Wort. The Lancet 2000;355: 547-548. 9) Henderson L, Yue Q, Bergquist C, Gerden B, Arlett P. St John’s Wort (Hypericum perforatum): Drug St. John’s Wort was found to be highly effective in relieving symptoms of depression versus placebo. However, a review of the current literature indicated that SJW has similar efficacy compared to seven standard prescription medications from both the neuronal uptake inhibitor and selective serotonin reuptake inhibitor (SSRI) classes of antidepressants. Depression is a prevalent disease affecting millions of people world-wide and alternative herbal medications are now being used more frequently as a result of lesser side effects. A comparison of St. John’s Wort, Hypericum perforatum, to seven other prescription medications showed similar efficacy with fewer adverse drug reactions. Hyperforin has been shown to be an uptake inhibitor of 5-hydroxytryptamine, dopamine, noradrenaline (norepinephrine), GABA and l-glutamate in synaptosomal preparations. A systematic review of current evidence concluded that Hypericum extracts are well tolerated and safe, aside from the potential for interactions with other drugs. St. John's Wort was associated with fewer and milder adverse reactions when compared with conventional antidepressants; however, a case report exists of an overdose of St. John's Wort in a patient requiring management in the intensive care unit. Overall, St. John’s Wort has a lot of evidence regarding drug interactions. This is an important piece of information, and with this, it is easier to make St. John’s Wort recommendations for those using it to treat depression. Depression is a serious disease that affects a significant portion of the population. While there are several prescription medications available to treat depression, many suffer from severe adverse effects. Furthermore, seeking psychiatric evaluation and taking prescription antidepressants carries with it an undesirable stigma that may be severe enough to preclude some patients from seeking help. Therefore, an herbal remedy available over the counter to treat depression has great potential for helping thousands of patients. St. John’s Wort has long been known for its potential antidepressant effects. However, its efficacy and safety have been controversial. In this study, St. John’s Wort was found to be highly effective in treating major depressive disorders in comparison to placebo. The mechanism of action has been found to be due to the inhibition of monoamine oxidase and substance-P effects. Furthermore, many contradicting studies have been published that compare St. John’s Wort to prescription medications. In this study the efficacy of St. John’s Wort for treating depression compared with several other prescription medications indicated that the herbal preparation has similar effects. Perhaps more importantly, St. John’s Wort was found to have significantly fewer reports of adverse drug effects as compared to prescription antidepressants, especially those which were bad enough to force the termination of treatment. Unfortunately, St. John’s Wort suffers from its high tendency for drug-drug interactions. Given these results, we can conclude that St. John’s Wort may be a viable option for treating depression for those who do not prefer prescription medications, especially if the patient is not currently taking other medications with which St. John’s Wort may interfere. Pharmacokinetic data is available for several of the compounds present in St. John’s Wort, which may be considered responsible for its antidepressant action. The following table summarizes some of the pharmacokinetic values for these compounds. t max is the time necessary to reach peak absorption, t 1/2 is the time required for 50% elimination, and NR stands for not reported. Treating Depression with St. John’s Wort (Continued) In February 2000, the FDA issued a public health advisory regarding the drug interaction between SJW and indinavir. Indinavir is a HIV-1 protease inhibitor that is metabolized by CYP3A4. In one study, it was shown that SJW reduced the area under the curve of indinavir by a mean of 57% (Piscitelli et. al). The mean concentration- time profiles of indinavir alone and SJW are shown in the accompanying figure. Drug-Drug Interactions (Continued) A comparison of the number of subjects reporting any adverse drug reaction (ADR) and the number of ADRs requiring discontinuation of treatment between SJW and standard antidepressants indicated that remarkably fewer events were reported for SJW. This result greatly favors SJW in terms of safety for treating depression. Hyperic in Limited information on genotoxicity exists. Potent inhibition of sperm motility was observed in vitro. An overdose of St. John's Wort has been documented in a 16-year-old patient consuming 15 tablets (300 mcg strength) per day for 2 weeks, requiring management in the intensive care unit. Depression is a common disease state that affects millions and often is under-diagnosed and under-treated on a global scale. The prevalence of the disease and the lack of diagnosis signify that there should be increased awareness of the symptoms associated with the disease and initiatives that can incorporate screenings for patients to properly diagnose depression. The World Health Organization has prompted initiatives in order to raise awareness of the disease and symptoms, which include feeling sad or worthless, loss of appetite, sleeplessness, and thoughts of suicide. From a pharmacologic perspective, depression can be caused from an imbalance of serotonin, noradrenaline (norepinephrine), and dopamine neurotransmitters. The first line drug treatments currently available include selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants. These types of antidepressants are helpful in managing the disease; however, unfavorable side effects and problems with medication adherence have resulted and alternative herbal medications have been implemented to treat the disease. St. John's Wort is the most influential and marketed herbal supplement for the treatment of depression. The plant is a member of the Hypericaceae family and is used to treat depressive disorders in many countries. The main active ingredient extracted from Hypericum perforatum is hypericin. The Hypericum perforatum extracts are proposed to have other significant constituents that could also be responsible for its pharmacologic effects. These constituents include thodiantrhons, flavonoids, bi-flavonoids, xanthons, and phloroglucinol derivatives. Many reports have indicated that St. John’s Wort interacts with a number of different medications, which can possibly lead to serious adverse reactions. However, the exact mechanisms behind these interactions are still being investigated. It has been suspected that the pharmacokinetic interactions identified are due to the induction of CYP450 enzymes and transport proteins such as P-glycoprotein. A summary of these drugs are presented in the table below.
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Transcript of Group12 poster2ndedit
TEMPLATE DESIGN © 2008
www.PosterPresentations.com
Treating Depression with St. John’s Wort: Therapeutic Breakthrough or Hidden Hazard?Elisa Bailey, Alissa Basehoar, Jeannie Kim, Rozine Lindamood, Lauren Pearson, Justin Siegfried, Tiffany VanDervort
Class of 2013 – School of Pharmacy – Virginia Commonwealth University
Abstract
Introduction
Pharmacokinetics/Pharmacodynamics
Hyperforin is the only compound listed that has been shown to cross the blood brain barrier in animal studies. Hyperforin is believed to be responsible for St. John’s Wort’s ability to non-selectively block neurotransmitter reuptake. It is also believed to be responsible for the many drug-drug interactions because it activates human pregnane X receptor, leading to increased drug metabolism by cytochrome P450 3A4. Hyperforin was also shown to increase the activity of CYP 1A2 and 2C9. There is also limited evidence that hyperforin induces the P-glycoprotein efflux transporter.
The two napthodiantrones present in St. John’s Wort are hypericin and pseudohypericin. Both of these compounds have low bioavailability due to their low water solubility. Hypericin treatment led to decreased plasma levels of adrenocorticotropic hormone and cortisol. High doses of hypericin can cause photosensitization to UV light, called hypericism.
The main flavonoids found in hypericum perforatum are the monoglycosides: quercitrin, isoquercitin, and hyperoside; and the diglycoside rutin. The flavonoids undergo extensive Phase II metabolism in the intestinal wall releasing the aglycoside, quercetin. Quercetin exhibits a double peak plasma profile with the first peak appearing after 1.5 hours and the second, lower peak, after 9 hours. Studies show that flavonoids present in St. John’s Wort weakly inhibit monoamine oxidase.
Treating Depression with St. John’s Wort
Pharmacology/Mechanism of ActionAlthough St. John’s Wort contains at least seven constituents that may contribute
to its pharmacological effects, hypericin and hyperforin are the major active constituents responsible for antidepressant effect.
Research initially focused on hypericin as the active component of St John's Wort exerting the herb's antidepressant effects. Early studies showed that St. John’s Wort inhibits monoamine oxidase-A (MAO-A) and MAO-B activity in rat brain mitochondria in vitro. Receptor binding and enzyme inhibition assays demonstrated significant receptor affinity of St. John’s Wort for adenosine, GABAA, GABAB, benzodiazepine and MAO-A,-B. It inhibits the uptake of serotonin (5-hydroxytrptamine; 5-HT), dopamine, and norepinephrine with approximately equal affinity and also shows a down-regulation of beta receptors and an up- regulation of 5-HT2 receptors in rat frontal cortex.
Hyperforin has now emerged as one of the major active constituents in St. John’s Wort’s antidepressive effects. Hyperforin has been shown to be an uptake inhibitor of 5-hydroxytryptamine, dopamine, noradrenaline (norepinephrine), GABA and l-glutamate in preparations and to inhibit 5-HTuptake in rat peritoneal cells in a dose-dependent manner. Studies have reported that the mechanism of action of hyperforin in serotonin uptake inhibition appears to be associated with an increase of free intracellular sodium ion concentrations and that this may be secondary to activation of Na+/H+ exchange as a result of a decrease in intracellular pH. Further in vitro experiments have demonstrated hyperforin does increase both intracellular sodium ion and calcium ion concentrations, and this is mediated through activation by hyperforin of non-selective cation channels.
Drug-Drug Interactions
Toxicity/Side EffectsA systematic review of current evidence concluded that Hypericum perforatum
extracts are well tolerated and safe, aside from the potential for interactions with other drugs. St. John's Wort was associated with fewer and milder adverse reactions when compared with conventional antidepressants. The commonly experienced side effects are listed below:
Conclusions
References
• Dry mouth• Nausea• Change in bowel habits• Itching• Photosensitization• Fatigue
• Dizziness• Jitteriness• Insomnia• Sleep disorders• Headache• Induction of mania
Drug Class Specific Example
Metabolism (major) Effect of interaction on drug
HIV protease inhibitor Indinavir CYP3A4
Reduction of AUC of indinavir by a mean of 57%. Reduction in exposure could lead
to development of drug resistance and treatment failure in HIV patients
Anticoagulant Warfarin CYP2C9Reduced anticoagulant effects. Monitor
INR values. May need to adjust dosages of anticoagulants.
Immunosuppressant Cyclosporin P-glycoprotein, CYP3A4
Subtherapeutic blood concentrations resulting in risk of rejection of the
transplanted organ. May need to adjust dosages of immunosuppressant.
SSRIs N/A CYP2C9Risk of serotonin syndrome (confusion,
agitation, shivering, tremor, nausea, diarrhea, lack of coordination, fever, rhabdomyolysis). Discontinue SJW.
Theophylline N/A CYP 3A4, CYP1A2
Reduced blood concentrations. Caution with asthma and pulmonary diseases.
Discontinue SJW.
Antiarrhythmic Digoxin P-glycoprotein Reduced blood concentrations. May affect heart rhythm. Discontinue SJW.
Oral Contraceptives N/A CYP3A4Reduced blood concentrations. Risk of unintended pregnancy and bleeding.
Discontinue SJW.
Compound Lag time (hrs) tmax (hrs) t1/2 (hrs) Steady State (days)
Hyperforin 1 3 – 3.5 9 NRHypericin 2 6 33 6 – 7
Pseudohypericin < ½ 3 21 4Monoglycosides NR < 1 NR NR
Rutin NR 7 NR NR
1) Baruch Y. Hypericum extract for treatment of depression: what's new?. Harefuah 2009;148(3):183-185,209-210.
2) Candy B, Jones L, Williams R, Tookman A, King. Psychostimulants for depression. Cochrane Database of Systemic Reviews 2008;2:3-32.
3) Delgado PL. Depression: the case for monoamine deficiency: Journal of Clinical Psychiatry 2000:61:7-11.
4) Kirsh I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration: PloS Medicine 2008:5:260-8.
5) Linde K, Berner MM, Kriston L. St John's Wort for Major Depression (Review). Cochrane Database of Systematic Reviews 2008;4.
6) Butterweck V. Mechanism of Action of St John's Wort in Depression: What is Known?. CNS Drugs 2003; 17(8):539-562.
7) National Institute for Clinical Excellence. Depression: management of depression in primary and secondary care. Clinical practice guideline No. 23. London: National Institute for Clinical Excellence, 2004.
8) Piscitelli S, Burstein A, Chaitt D, Alfaro R, Falloon J. Indinavir Concentrations and St John’s Wort. The Lancet 2000;355: 547-548.
9) Henderson L, Yue Q, Bergquist C, Gerden B, Arlett P. St John’s Wort (Hypericum perforatum): Drug Interactions and Clinical Outcomes. J Clin Pharmacol 2002;54:349-356.
10) Wurglics M, Schubert-Zsilavecz M. Hypericum Perforatum: A Modern Herbal Antidepressant: Pharmacokinetics of Active Ingredients. Clin Pharmacokinet 2006;45(5):449-468.
St. John’s Wort was found to be highly effective in relieving symptoms of depression versus placebo. However, a review of the current literature indicated that SJW has similar efficacy compared to seven standard prescription medications from both the neuronal uptake inhibitor and selective serotonin reuptake inhibitor (SSRI) classes of antidepressants.
Depression is a prevalent disease affecting millions of people world-wide and alternative herbal medications are now being used more frequently as a result of lesser side effects. A comparison of St. John’s Wort, Hypericum perforatum, to seven other prescription medications showed similar efficacy with fewer adverse drug reactions. Hyperforin has been shown to be an uptake inhibitor of 5-hydroxytryptamine, dopamine, noradrenaline (norepinephrine), GABA and l-glutamate in synaptosomal preparations. A systematic review of current evidence concluded that Hypericum extracts are well tolerated and safe, aside from the potential for interactions with other drugs. St. John's Wort was associated with fewer and milder adverse reactions when compared with conventional antidepressants; however, a case report exists of an overdose of St. John's Wort in a patient requiring management in the intensive care unit. Overall, St. John’s Wort has a lot of evidence regarding drug interactions. This is an important piece of information, and with this, it is easier to make St. John’s Wort recommendations for those using it to treat depression.
Depression is a serious disease that affects a significant portion of the population. While there are several prescription medications available to treat depression, many suffer from severe adverse effects. Furthermore, seeking psychiatric evaluation and taking prescription antidepressants carries with it an undesirable stigma that may be severe enough to preclude some patients from seeking help. Therefore, an herbal remedy available over the counter to treat depression has great potential for helping thousands of patients.
St. John’s Wort has long been known for its potential antidepressant effects. However, its efficacy and safety have been controversial. In this study, St. John’s Wort was found to be highly effective in treating major depressive disorders in comparison to placebo. The mechanism of action has been found to be due to the inhibition of monoamine oxidase and substance-P effects.
Furthermore, many contradicting studies have been published that compare St. John’s Wort to prescription medications. In this study the efficacy of St. John’s Wort for treating depression compared with several other prescription medications indicated that the herbal preparation has similar effects. Perhaps more importantly, St. John’s Wort was found to have significantly fewer reports of adverse drug effects as compared to prescription antidepressants, especially those which were bad enough to force the termination of treatment. Unfortunately, St. John’s Wort suffers from its high tendency for drug-drug interactions. Given these results, we can conclude that St. John’s Wort may be a viable option for treating depression for those who do not prefer prescription medications, especially if the patient is not currently taking other medications with which St. John’s Wort may interfere.
Pharmacokinetic data is available for several of the compounds present in St. John’s Wort, which may be considered responsible for its antidepressant action. The following table summarizes some of the pharmacokinetic values for these compounds.
tmax is the time necessary to reach peak absorption, t1/2 is the time required for 50% elimination, and NR stands for not reported.
Treating Depression with St. John’s Wort (Continued)
In February 2000, the FDA issued a public health advisory regarding the drug interaction between SJW and indinavir. Indinavir is a HIV-1 protease inhibitor that is metabolized by CYP3A4. In one study, it was shown that SJW reduced the area under the curve of indinavir by a mean of 57% (Piscitelli et. al). The mean concentration-time profiles of indinavir alone and SJW are shown in the accompanying figure.
Drug-Drug Interactions (Continued)A comparison of the number of subjects reporting any adverse drug reaction
(ADR) and the number of ADRs requiring discontinuation of treatment between SJW and standard antidepressants indicated that remarkably fewer events were reported for SJW. This result greatly favors SJW in terms of safety for treating depression.
Hypericin
Limited information on genotoxicity exists. Potent inhibition of sperm motility was observed in vitro. An overdose of St. John's Wort has been documented in a 16-year-old patient consuming 15 tablets (300 mcg strength) per day for 2 weeks, requiring management in the intensive care unit.
Depression is a common disease state that affects millions and often is under-diagnosed and under-treated on a global scale. The prevalence of the disease and the lack of diagnosis signify that there should be increased awareness of the symptoms associated with the disease and initiatives that can incorporate screenings for patients to properly diagnose depression. The World Health Organization has prompted initiatives in order to raise awareness of the disease and symptoms, which include feeling sad or worthless, loss of appetite, sleeplessness, and thoughts of suicide. From a pharmacologic perspective, depression can be caused from an imbalance of serotonin, noradrenaline (norepinephrine), and dopamine neurotransmitters. The first line drug treatments currently available include selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants. These types of antidepressants are helpful in managing the disease; however, unfavorable side effects and problems with medication adherence have resulted and alternative herbal medications have been implemented to treat the disease.
St. John's Wort is the most influential and marketed herbal supplement for the treatment of depression. The plant is a member of the Hypericaceae family and is used to treat depressive disorders in many countries. The main active ingredient extracted from Hypericum perforatum is hypericin. The Hypericum perforatum extracts are proposed to have other significant constituents that could also be responsible for its pharmacologic effects. These constituents include thodiantrhons, flavonoids, bi-flavonoids, xanthons, and phloroglucinol derivatives.
Many reports have indicated that St. John’s Wort interacts with a number of different medications, which can possibly lead to serious adverse reactions. However, the exact mechanisms behind these interactions are still being investigated. It has been suspected that the pharmacokinetic interactions identified are due to the induction of CYP450 enzymes and transport proteins such as P-glycoprotein. A summary of these drugs are presented in the table below.
