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.