Module 41 Flashcards
Is depression caused by a deficiency of serotonin? What fraction of patients have a long term benefit from antidepressants?
- Although SSRIs have efficacy in the treatment of depression, depression is not simply a deficiency in serotonin
- Antidepressants have limited efficacy in mild depression. Most patients with severe depression do not have a sustained response to antidepressants; however, severe depression can be devastating, and for those who do have a sustained respond, maybe 20%, antidepressants can be life-saving.
Some of the SSRIs (selective serotonin reuptake inhibitors) bind to CYP 2D6 with high affinity. How may that lead to drug interactions? How would you decide when it is an important issue? What other structural feature of paroxetine makes it a good P-450 inhibitor?
- Several of the SSRIs are potent inhibitors of CYP2D6. This inhibition is important when the inhibitor has a higher affinity for the P450 than the co-administered drug because most are competitive inhibitors. Such inhibition is also only important if the metabolism of the drug by CYP2D6 is important, i.e. it is the major mode of clearance, or it is responsible for bioactivation of a prodrug.
- Furthermore, the inhibition is most important for drugs that have a narrow therapeutic index, i.e. a small change in the concentration can lead to therapeutic failure or toxicity. In addition, paroxetine contains a methylene dioxy group (left side of the molecule). This is oxidized to a reactive carbene (divalent carbon), which is a potent irreversible P450 inhibitor. We covered this in PHM144 and a previous question.
Why does it take more than a week for antidepressants to work, and what new type of agent appears to have effects much more quickly?
- The reason for the delay in response to antidepressants is not well understood.
Ketamine and related agents work much more rapidly, and there is a major effort to develop agents that work like ketamine but do not have the neurological side-effects of ketamine such as hallucinations
Can antidepressants lead to suicide?
This is a complex issue. There are many case reports in which antidepressants appear to have led to suicide. However, the population being treated is at increased risk of suicide, and it is difficult to differentiate the effects of the antidepressants from the underlying condition being treated. Many antidepressants have “Black Box” warnings with respect to suicide, and caution is appropriate. This appears to be more of a problem in patients younger than 25
What are the hazards in switching from a SSRI to a MAO inhibitor antidepressant? What are the hazards of providing pain relief to a patient who is on a MAO inhibitor?
- Switching from a SSRI to a MAO inhibitor can result in serotonin syndrome. For example the desmethyl metabolite of fluoxetine (norfluoxetine, formed by N-demethylation) is also active, and it has a half-life of 1-2 weeks. Therefore, if you started a MAO inhibitor immediately after stopping fluoxetine you would have the effects of both drugs. Some opiates such as demerol can also cause the serotonin syndrome when combined with an MAO inhibitor.
What herbal product is said to be useful for the treatment of depression, and what is the evidence of efficacy? What are the side-effects? By what mechanism does it lead to potential drug interactions?
- There are studies that found that St. John’s wort was as effective as other antidepressants. It appears to have fewer side-effects than other antidepressants, but it is a very potent inducer of P450 and p-glycoprotein, and this has led to many serious drug interactions.
What drugs appear to cause depression in some patients?
- Interferon used to treat hepatitis B almost always causes depression, and some physicians start an antidepressant along with the interferon.
- Reserpine, an old drug used to treat hypertension, was notorious for causing depression. There are several cases of suicide associated with the use of isotretinoin; however, this association is more controversial. Several drugs that are used to treat hypertension such as alpha-methyldopa and even propranolol can cause depression.
What antidepressants are associated with an increased risk of bleeding and what is the mechanism?
The mechanism is not well understood, but serotonin is stored in platelets. It is released during the formation of blood clots and stimulates platelet aggregation. Platelets are not whole cells and cannot synthesize serotonin; therefore, they rely on serotonin uptake from the plasma. SSRIs inhibit this uptake, and therefore decrease platelet aggregation. This leads to an increase in the risk of serious GI bleeds and increases the need for blood transfusions during surgery. SSRIs are even suspected to be able to cause CNS microbleeds.
Lithium is a very useful drug for the treatment of bipolar disorder, especially mania. However, clinicians often avoid its use because it has a very narrow therapeutic range, and dosage is based on blood levels. Describe its pharmacokinetics. How is it cleared, and what affects clearance?
even though lithium is a metal ion and is 100% ionized, it is well absorbed, and it gets into the brain (otherwise it would not work). However, equilibrium between blood and brain is reached slowly. When the drug is stopped, the initial rate of disappearance is rapid with a half-life of ~10 hours, but then there is a slower phase of ~10-14 days.
- Obviously being a metal ion, lithium cannot be metabolized; it is cleared by the kidneys. Lithium clearance is increased by sodium and decreased by hyponatremia; therefore, loop diuretics and thiazide diuretics that increase sodium clearance, decrease lithium clearance.
Lithium clearance can also be decreased by ACE inhibitors. In contrast to loop and thiazide diuretics, lithium clearance is increased by osmotic diuretics.
