How come certain drugs (i.e. antidepressants) take days/weeks before they work?

[Skorpio]

Unsurprisingly it's not often prescribed for depression

Probably due to it's dopamine antagonism

It’s honestly weird it’s considered an antidepressant (guess it’s tricyclic heritage carries a lot of weight there), because it seems to be a pretty quintessential atypical antipsychotic.

I guess it beat abilify to the punch by quite a long bit as an antipsychotic indicated for MDD.

 

[Conky]

It’s honestly weird it’s considered an antidepressant (guess it’s tricyclic heritage carries a lot of weight there), because it seems to be a pretty quintessential atypical antipsychotic.

I guess it beat ability to the punch by quite a long bit as an antipsychotic indicated for MDD.

Supposedly amoxapine's antidepressant properties are thought to be primarily due to NET inhibition but that's nothing new as the secondary amine tricyclics have strong affinity for NET without antidopaminergic properties.

I think it's a little weird that various atypical antipsychotics including aripiprozole are used as adjunctive therapy with SSRIs given the high rates of sexual dysfunction and other unwanted effects those drugs are known to cause. Over 5 decades of antidepressant development and not a single compound on the market with strong and selective DAT inhibition. Seems a little sus.

 

[red22]

Over 5 decades of antidepressant development and not a single compound on the market with strong and selective DAT inhibition. Seems a little sus.

Find out why YOU need dopamine and why MAOIs are essential. @psychotropicalresearch5653, 2020-06-22, YouTube

 

[Skorpio]

Supposedly amoxapine's antidepressant properties are thought to be primarily due to NET inhibition but that's nothing new as the secondary amine tricyclics have strong affinity for NET without antidopaminergic properties.

I think it's a little weird that various atypical antipsychotics including aripiprozole are used as adjunctive therapy with SSRIs given the high rates of sexual dysfunction and other unwanted effects those drugs are known to cause. Over 5 decades of antidepressant development and not a single compound on the market with strong and selective DAT inhibition. Seems a little sus.

People are really scared of abuse potential, so if a class of drugs is generally non-reinforcing, it is an uphill battle to get something approved that is reinforcing.

 

[red22]

Not completely unreasonable: drug users have given drugs a very bad reputation over the years. Researchers are looking for that miracle pill that just works entirely in the background, making your life better (i.e., magic…luck…).

 

[Conky]

Be that as it may, a dopaminergic medication (or 2) might be the only thing resistant depression will respond to in some patients

Shouldn't be an issue considering opioid users get bupe and methadone and even IV diacetyl morphine in select locations

 

[Smyth2]

Consider this patent on nifedipine augmentation strategy:

"Another disadvantage of some known antidepressants is the relatively late onset of action, which is often not observed in a satisfactory manner until some days after the first administration. A potentiation of the action with a simultaneous reduction in the amount of active compound makes it possible to achieve an earlier onset of the desired effect."

Jorg Traber & Harald Horstmann, US4956361 (1990 to Bayer AG).

Another reference points to augmentation of an SSRI with 5-HT1a autoreceptor antagonist:

"Driven by the success of the SSRIs, it has been a popular strategy to pursue various augmentation principles to serotonin (5-HT) reuptake inhibition, thereby hoping to improve on some of the shortcomings of the SSRIs. Fast onset of action, in particular, has been in focus [9]."

Moltzen EK, Bang-Andersen B. Serotonin reuptake inhibitors: the corner stone in treatment of depression for half a century--a medicinal chemistry survey. Curr Top Med Chem. 2006;6(17):1801-23. doi: 10.2174/156802606778249810. PMID: 17017959.

Adell A, Castro E, Celada P, Bortolozzi A, Pazos A, Artigas F. Strategies for producing faster acting antidepressants. Drug Discov Today. 2005 Apr 15;10(8):578-85. doi: 10.1016/S1359-6446(05)03398-2. PMID: 15837601.

 

[Smyth2]

I just discovered an antidepressant in clinical development with a faster onset of action compared with conventional antidepressants.

The drug is called Ropanicant.

 

[Rectify]

Because they don't.

 

[4DQSAR]

I just discovered an antidepressant in clinical development with a faster onset of action compared with conventional antidepressants.

The drug is called Ropanicant.

https://www.flcompany.info/companies/F23000006373/
I always like to take a look at startups such as their date of incorporation, principal address (streetview) and stock market interest. Along with their website.

Home

So new, much interest, a little opaque. Odd that the URL was seemingly registered in 2017 but seeminly unused for quite a while.

It's interesting but for some reason details like the website not being secure rhat I've seen when cost is being very tightly controlled. I mean, no privilaged data so I accept it isn't required, but it's just sort of usual that in the west, we all use it. It's the US subsiduary of an Indian company. Does that have advantages when it comes to dealing with the FDA? I don't know. Certainly US investors are interested.

Interesting target and I'm glad SOMEONE is still working on it.

I've never forgotten that when the SSRIs were clinically tested, they would compare the highest dose prescribable of the new medication with the lowest dose of amitryptaline. So I am aware that one has to read the smallprint of studies. I guess SSRIs were popular mostly because in overdose (depressed patients can intentionally do this), most SSRIs were vastly safer than tricyclics. Faster onset is good... but it's not actually new.

 

[Bobbyrobbydo]

Because they don't.

I honestly believe you are accurate in your response to this question. While we can measure serotonin in the blood, platelets, or urine, these numbers don’t correlate well with levels in the brain. The blood-brain barrier keeps central and peripheral serotonin pools largely separate, making even that test unreliable. The brain’s serotonin levels can only be meaningfully measured using invasive micro dialysis, experimental imaging, and/or research-based technologies. These are not standard-of-care, not routinely done in humans, and often limited to animal studies or highly controlled research settings, meaning those prescribers are making a decision to prescribe the anti-depressant based on signs and symptoms alone. It's after you begin taking them, that the real research begins because then they just watch your responses to the medication and titrate the drug up or down, whichever direction that indicates. I do believe your answer is correct though, they Don't work. Modern Quackery

 

[4DQSAR]

I honestly believe you are accurate in your response to this question. While we can measure serotonin in the blood, platelets, or urine, these numbers don’t correlate well with levels in the brain. The blood-brain barrier keeps central and peripheral serotonin pools largely separate, making even that test unreliable. The brain’s serotonin levels can only be meaningfully measured using invasive micro dialysis, experimental imaging, and/or research-based technologies. These are not standard-of-care, not routinely done in humans, and often limited to animal studies or highly controlled research settings, meaning those prescribers are making a decision to prescribe the anti-depressant based on signs and symptoms alone. It's after you begin taking them, that the real research begins because then they just watch your responses to the medication and titrate the drug up or down, whichever direction that indicates. I do believe your answer is correct though, they Don't work. Modern Quackery

We can take samples of cerbrospinal fluid. That's usful because not only does it give us some idea of the levels of the drug that are inside the BBB but it may also identify metabolites which, for whatever reasons, cannot pass through the BBB.

But we still don't fully understand why a person may be suffering from clinical depression. It's also the case that there are a group of associated symptoms that have themselves become medicalized. That's why in the UK we still use the DSM IIIa. Clinicians noted who was funding studies into mental illness and noted examples such as General Anxiety Disorder suddenly becoming a seperate illness. Would it surprise you to learn that the patent-holder of alprazolam (at the time the only medication licenced for the treatment of GAD) paid for the studies that identified GAD? The list is long and ignoble.

I always wondered why, if the 'problem' with tricyclics was that their toxicity, doctors didn't simply make the patient pick up their prescription up on a weekly basis. Sure, someone could hoard medication but if someone is able to plan zelfmoord that far in advance, they will find another way.

I knew someone who had their medication delivered on a weekly basis. I didn't ask but I got to hear the precice dosage of each medication as did the other twenty three students in the room. Over the months this person displayed behaviors I would not associate with depression. An example would be my turning up with my arm in a cast which I did not allude to. Yet the whole room got to hear about how badly the hospital had treated this other person. They managed to alienate every single other student within a few weeks. Apropos of nothing, we got to hear every problem this person was experiencing and why in every case, it was entirely someone else's fault. Everything was about them.

So is that clinical depression or is it something else where depression may be a symptom? Not my field so I don't know. But it seemed much more like someone who WAS unhappy but whose sole consolation was to make others unhappy.

 

[Conky]

We can take samples of cerbrospinal fluid. That's usful because not only does it give us some idea of the levels of the drug that are inside the BBB but it may also identify metabolites which, for whatever reasons, cannot pass through the BBB.

But we still don't fully understand why a person may be suffering from clinical depression. It's also the case that there are a group of associated symptoms that have themselves become medicalized. That's why in the UK we still use the DSM IIIa. Clinicians noted who was funding studies into mental illness and noted examples such as General Anxiety Disorder suddenly becoming a seperate illness. Would it surprise you to learn that the patent-holder of alprazolam (at the time the only medication licenced for the treatment of GAD) paid for the studies that identified GAD? The list is long and ignoble.

I always wondered why, if the 'problem' with tricyclics was that their toxicity, doctors didn't simply make the patient pick up their prescription up on a weekly basis. Sure, someone could hoard medication but if someone is able to plan zelfmoord that far in advance, they will find another way.

I knew someone who had their medication delivered on a weekly basis. I didn't ask but I got to hear the precice dosage of each medication as did the other twenty three students in the room. Over the months this person displayed behaviors I would not associate with depression. An example would be my turning up with my arm in a cast which I did not allude to. Yet the whole room got to hear about how badly the hospital had treated this other person. They managed to alienate every single other student within a few weeks. Apropos of nothing, we got to hear every problem this person was experiencing and why in every case, it was entirely someone else's fault. Everything was about them.

So is that clinical depression or is it something else where depression may be a symptom? Not my field so I don't know. But it seemed much more like someone who WAS unhappy but whose sole consolation was to make others unhappy.

What kind of medications was that person taking?

 

[4DQSAR]

What kind of medications was that person taking?

Oh, a whole raft of things but if I am remembering it right (this was 25+ years ago) they were prescribed amitryptaline, lithium citrate, paracetamol compounded with methionine (prescribed to patients judged to be a suicide risk - the methionine stops paracetamol poisoning), 2mg diazepam TID and something else. I forget what, but it seemed like they believed we should understand and forgive their behaviors BECAUSE they were on (IMO inappropriate) medications.

In such cases, medicines are rarely of value. It's long-term therapy led by someone with the appropriate education and experience.

I think the medication was inappropriate but the fact that the person's GP either didn't spot or didn't consider that the symptoms could equally fit something quite different seemed odd to me. But who knows what that person's relationship with their doctor was? I suspect they were a 'frequent flyer' and the GP just added a medication as yet another symptom was trotted out.

 

[highabdl]

I think your GP was probably just making that up cos they didn't know.

We don't know why they take so long to work. There are only theories. The levels of serotonin in the blood increases within hours of taking them. But for some reason you have to have maintained that level for weeks to months before getting any benefit.

As some have said there's actually not that much evidence that SSRIs or really any antidepressants do work at all, they're only slightly more effective than placebo.

Actually shockingly little is known about the pharmacology and basic science of these psychotropic medications.

 

[4DQSAR]

I think your GP was probably just making that up cos they didn't know.

Not my GP. Read the thread.