Psycho-Babble Medication Thread 1113112

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Dose increase recommendations vs time for effect?

Posted by Mtom on December 26, 2020, at 12:07:37

I frequently read dosing schedules prescribed for Antidepressants suggest starting at a low to moderate dose, then increasing every 1 to 2 weeks until effect.

What about the fact that it takes most antidepressants 4 to 6 weeks to even kick in (and possibly longer - I've read articles that claim studies have shown for some people it can take up to 8 to 12 weeks to feel better)?

Patients are being told to increase their dose before knowing whether the lower dose would work. Which could in some cases increase the potential for adverse effects. There is of course an urgency to feel better quickly, is this what is driving an increasing dosing schedule which is faster than the time for effect?

I read one paper commenting that some Doctors say that often when they reduce patients from higher to lower doses, the depression returns. The author questioned whether this was in fact a return of the original depression, or antidepressant withdrawal symptoms.

So why is it often prescribed to increase dose after 1 to 2 weeks, and continue this increase schedule up to a specified maximum - when the initial dose (or even the first or second increase if occurring within the first 4 to 6 weeks) have not been given time to assess the effect at these lower doses?

One paper published in the Lancet in July 2019 showed that efficacy starts to decrease above a certain moderate dose, while adverse effects increase. See https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(19)30217-2/fulltext and scroll down to Figures 2, 3 and 4.

I found the u-shaped efficacy curve for Mirtazapine (Figure 4) particularly interesting as I have experienced this - I have a partial but noticeable response on low doses (below the peak shown in this curve, but I am ultra-sensitive). In an effort to increase my response, my doctors keep encouraging me to increase dose. However every time I've tried, both the side effects and the depression worsen.

A P-Doc I've seen in past mentioned this u-shaped curve is known for many AD medications. So again, why are patients told to keep increasing dose in the early weeks and months of starting an AD without waiting long enough to see if lower to moderate doses are effective?

 

Re: Dose increase recommendations vs time for effect?

Posted by linkadge on December 26, 2020, at 13:44:50

In reply to Dose increase recommendations vs time for effect?, posted by Mtom on December 26, 2020, at 12:07:37

Interesting conversation ...

I often wonder these things myself. I also wonder these things in the context of 'rapid acting' antidepressants.

A therapist once told me ... "You didn't become depressed overnight, so don't expect to get better overnight". I have heard variations of this many times over the years. But the question is whether or not it's true.

The notion that the brain needs time to 'heal' is likely true to an extent. However, things like ketamine, sleep deprivation, ECT can work very quickly.

It is difficult to say why the time / dose course can vary from person to person. With standard antidepressants, some people feel better in a week, while others need weeks or months. In studies I have read, mirtazapine does appear to work relatively rapidly, but (as you mention) different doses can have different effects.

I think in many cases, the highest *tolerated* dose is probably best (at least, for severe depression). Some of the adaptive changes probably happen quicker at a higher dose. But you also need to consider other factors like side effects. If the patient is overwhelmed by side effects, they may not wait for a response. Conversely, if they have to wait too long, they may also not respond. As you mention too, not all antidepressants have a linear dose/response relationship. Or (depending on the patient) higher doses may start to be counterproductive. For example, effexor becomes more noradrenergic at higher doses. This may help some patients but make others worse.

You kind of have to play around with different doses yourself and then be assertive with your doctor. I know (in the old days) recommendations for nardil were to initiate with a high dose (until remission) and then lower down to a maintenance dose (i.e. 15-30mg).

Linkadge

 

Re: Dose increase recommendations vs time for effect?

Posted by rjlockhart37 on December 26, 2020, at 19:59:56

In reply to Dose increase recommendations vs time for effect?, posted by Mtom on December 26, 2020, at 12:07:37

I think some doctors are 'pushy' with getting people bumped up on doses, they will skyrocket the dose on people. Like years ago, I was asking my psychiatrist abobut Lyrica, i told him i heard about it, he immidnatly said no, nuerontin, and he wrote a scrpt for 800mg X 3 daily, i didnt start it at the dose, but i had half the tablets, then move up to 800mg tablet.

Right now i take 600mg of nuerontin, my doctor said its the maximum. She is not in favor moving any higher. But the previous doctor was pushy, and wrote the script for 800mg, it was a rehab that was very expensive, they had only a few patients. We did therapy, talk with therapist, then see the psychiatrist. It was in a office type building where their offices were located.

Prozac I have to have it at maximum - 80mg because my depression is not responsive to 40, or 60. We went through years of trying wellbutrin, then finally giving the ok to bump it to 80. Prozac is the longest SSRI, to take effect, it takes i think about solid, 6-7 weeks to feel its antidepressant effect. Maybe some at 4 weeks. I think, in my case i have to have higher doses of meds, because i'm resistant in someway to meds, they have to bumped up.

Other people ths doenst really apply, because someone can start prozac at 20mg, and be fine without having to move to 40.

It's mainly about pushy doctors, they like doing extreme changes

 

ADs vs ketamine linkadge

Posted by Mtom on December 27, 2020, at 10:17:40

In reply to Re: Dose increase recommendations vs time for effect?, posted by linkadge on December 26, 2020, at 13:44:50

> The notion that the brain needs time to 'heal' is likely true to an extent. However, things like ketamine, sleep deprivation, ECT can work very quickly. >
> Linkadge
>

However my understanding is that ketamine and ECT are usually given in the context of treatment resistant depression when Antidepressants have not worked even after an adequate trial period (something which is discussed in the above conversation), typically with several different medications.

Which would lead one to believe that those patients depression was not being caused by lack of the usual neurotransmitters the AD's (supposedly) increase activity of and that some other cause and mechanism is involved which responds to ketamine or ECT.

Also, although I had previously heard that some do in fact respond quickly and well to ketamine, this new Nov 2020 paper examining response to ketamine in 85 patients at one centre found rather dismal response rates. 47 (40%) discontinued during or right after the 3 week induction phase. Another 14 (16.5%) discontinued during the maintenance phase. The paper says 3 of 85 discontinued due to side effects, but in the abstract does not say why the 47 discontinued during/after induction.

Fifteen out of 82 patients (18.3%) responded to induction treatment and 6 (7.3%) remained in responder status at the time of data analysis during maintenance. Despite the low response rates and the considerable cost of treamted, the authors noted that almost half the outpatients decided to continue with maintenance ketamine treatment due to perceived significant improvement. (Which is difficult to explain).
https://www.psychiatryadvisor.com/home/topics/mood-disorders/depressive-disorder/use-of-acute-and-maintenance-intravenous-ketamine-in-outpatients-with-trd/
https://www.sciencedirect.com/science/article/abs/pii/S0165032720325349?via%3Dihub

 

Re: Dose increase recommendations vs time for effect?

Posted by Mtom on December 27, 2020, at 10:52:05

In reply to Re: Dose increase recommendations vs time for effect?, posted by rjlockhart37 on December 26, 2020, at 19:59:56

My concern is, if you look at the paper linked in the initial post, including the graphs, SSRIs and Mirtazapine show an inverted u-shaped curve with highest efficacy in the mid-dose ranges, which started reducing in higher dose ranges, i.e. improvements in depression were (on average) lower at higher doses. This is interesting and relevant, and I don't see an explanation for this. Only venlafaxine did not show a strong inverted u-shaped curve for dose vs efficacy. In contrast, dropouts due to adverse effects increased linearly or exponentially with increasing dose for all the antidepressants examined (including venlafaxine).

Which suggests that if doses are being increased, as they often are, early after starting, during the phase in which there may not have been enough time to assess response, some patients may already be at doses in the downward portion of the efficacy curve before efficacy has had a chance to kick in, and all patients would be in the increasing adverse effects slope of the graphs.

The authors note that a previous study showed approximately 80% serotonin transporter occupancy occurs at minimum therapeutic doses of several SSRIs and venlafaxine, and that further dose increments result in only small increases in occupancy . Their data also suggests that increases over 80% occupancy dont result in greater efficacy.

It should be noted that this study was a Meta-Analysis of prior published studies. It sounds like most of those studies analyzed various fixed-doses of anti-depressants with no or rapid titration. They discuss tolerability might then confound efficacy because interventions with high dropouts are likely to show lower endpoint efficacy because the majority of patients leave the study early and therefore have less time to improve. Which still supports my point that a fast titration schedule in real clinical practice, increasing the dose too quickly, could do the same. Either through increasing adverse effects at the higher doses (which may have been more tolerable at lower doses) - or by dipping into the left decreasing slope of efficacy with the higher doses. Or both.

The authors conclude that for the majority of patients receiving SSRIs, venlafaxine, or mirtazapine for acute-phase major depression treatment, the lower range of the licensed dose likely achieves optimal balance between efficacy, tolerability, and acceptability.

The link again: https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(19)30217-2/fulltext Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis: Lancet Psychiatry. 2019 Jul;6(7):601-609. doi: 10.1016/S2215-0366(19)30217-2.

 

Re: Dose increase recommendations vs time for effect?

Posted by undopaminergic on December 27, 2020, at 15:55:49

In reply to Re: Dose increase recommendations vs time for effect?, posted by Mtom on December 27, 2020, at 10:52:05

I agree with your concern about "over-shooting" the optimal dose.

-undopaminergic

 

Re: ADs: Overshooting the optimal dose? undopaminergic

Posted by Mtom on December 28, 2020, at 11:55:03

In reply to Re: Dose increase recommendations vs time for effect?, posted by undopaminergic on December 27, 2020, at 15:55:49

> I agree with your concern about "over-shooting" the optimal dose.
>
> -undopaminergic
>

Yes undopaminergic, that is my concern and I've changed the heading to show your comment in order to invite further discussion. The rush to get to an "effective" dose, without really knowing what that dose is for each individual, may be contributing to lack of efficacy, adverse effects, and drop-outs.

Other factors that are increasingly being written about dosing include:

- Pharmacogenomics-Pharmacogenetics: Variant and mutant alleles, for example those that code for the various liver P450 enzymes involved in drug metabolism are increasingly being researched in the context of dosing, efficacy and adverse effects. I had Genetic Testing for medications 2 1/2 years ago - the data was more limited than anticipated (not quite ready for prime time was how my Doctor put what she had heard about these tests). However it did find that 1 of my 2 alleles for CYP2D6, involved in the metabolism of many drugs including most ADs is non-functional making me an Intermediate metabolizer for drugs metabolized by this enzyme. Other enzymes and genes are also involved in drug distribution and metabolism and I'm betting there are a significant number of people for whom this might be relevant (as indicated by growing research into this).

- Drug, and even supplement and food pharmacokinetic interactions. Food, supplements and other drugs can impact how a drug is metabolized - and variants-mutations such as the above can increase these interactions. A well known example: Grapefruit juice can block the action of the P450 enzyme CYP3A4 which metabolizes many drugs, so more of the drug enters the blood and stays in the body longer. The result: too much drug in your body. Other drugs, supplements and foods can also either increase or decrease the activity of various metabolizing enzymes resulting in too little or too much of a drug in the body with a standard dose. Again there is increasing research on this being published. (But not enough, likely due to lack of funding.)

- Sex Differences: A number of papers have been written on this. Doses prescribed do not typically account for differences in size, weight, body fat composition. In addition it has been found that females metabolize many drugs differently than males, a variety of examples have been written about. In general and on average, it has been noted that females develop more adverse effects than males for many drugs.

I see "Personalized Medicine" being written about as the wave of the future to address some of these issues. However this will be expensive and take much time per individual, I don't see it happening any time soon.

I don't think Dr. Bob comments frequently, if at all, on posts however it would be interesting to hear his thoughts on this.....

 

Re: ADs vs ketamine

Posted by linkadge on December 30, 2020, at 14:32:03

In reply to ADs vs ketamine linkadge, posted by Mtom on December 27, 2020, at 10:17:40

Yes, that is possible (different patients responding to different mechanisms).

That being said, the evidence for the monoamine hypothesis is very weak. Close to 70 years of studies have not found any conclusive evidence of a serotonin deficit, for example. That's not to say that that serotonergic system is not involved.

A new theory, involving g-proteins in lipid rafts appears to be promising. This study suggests that standard SSRIs cause alterations in lipid rafts that take days to weeks for effect, whereas ketamine produces the same changes within minutes or hours.

https://www.sciencedaily.com/releases/2018/06/180621172450.htm

Ketamine also causes regional changes in glutamate function that also happen with SSRIs (albeit in a much slower fashion).

Interestingly, failure of standard ADs is a predictor of failure to ECT. I would imagine that if ECT was used as a front line treatment, it would work rapidly for ~70% of patients. If you took a pool of resistant patients, then the efficacy would be much lower.

Other fast acting agents include SAMe (within days) or agmatine (within hours).


Linkadge


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