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I am having to go without Concerta till the lockdown ends. I do feel slightly upset because of this. I was doing fine while on it but off it I feel helplessness and anger. Somehow when I take Divalproex Sodium, these feelings are alleviated.
 

Is it my imagination or could this actually be helping.

 

Cheers!

Edited by the maze runner
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  • 3 weeks later...

@the maze runner well I'm sure you know that methylphenidate and valproate are two completely different compounds and work very differently in the brain and even feel quite different to the individual, they can both mediate similar downstream changes.

For example, bupropion (Wellbutrin) is regarded as a much more stimulating antidepressant and is structurally related to amphetamines and other stimulants like methylphenidate. It is a norepinephine-dopamine reuptake inhibitor like stimulants and a modest releasing agent of these neurotransmitters as well. This causes desensitization of the dopamine system and is inherently stabilizing as a result. The same concept is applied with serotonergic antidepressants and also explains why they can make things worse in the beginning (insomnia, increased anxiety, irritability). Serotonergic activation can mediate many of our mental illnesses. So ramping that up and desensitizing the brain to that signaling can quiet the downstream thought processes.

Where stimulants and bupropion stabilize the dopamine system via increased dopamine signaling and desensitization much like serotonergic antidepressants, valproate on the other hand actually attempts to directly calm the brain on various different levels.

1. It inhibits GABA transaminase and succinate-semialdehyde dehydrogenase which degrade GABA in the brain. Because GABA is the main calming/"depressant" neurotransmitter in the brain, this causes an increase in basal GABA levels.

2. It modulates but generally increases the activity of glutamate dehydrogenase, which would catalyze the conversion of glutamate back into GABA. Because glutamate is a primary excitatory neurotransmitter in the brain, this has a direct calming effect. Glutamate is implicated in some depressive disorders with marked anxious distress as well as bipolar disorder. By inhibiting GABA's breakdown in #1 and inducing glutamate's conversion into GABA here, further increases in basal GABA levels are realized.

3. It induces monoamine oxidase A which is chiefly responsible for the breakdown of monoamines like serotonin and to a lesser extent norepinephrine and dopamine. This results in lower serotonin signaling.

4. Via some mechanism, it reduces catecholamine synthesis (i.e. norepinephrine and dopamine)

The net results though is that valproate administration can actually INCREASE norepinephrine and dopamine concentrations in certain brain areas and decrease it in others. While these two medications are miles apart, perhaps for you they both mediate similar changes in your brain that make you feel better.

Another possibility is that after continued methylphenidate treatment you may be experiencing a bit of neurotransmitter depletion. This is something that everyone who takes stimulants goes through every day. They start the day with a ramp up in virtually all neurotransmitters, then they plummet as the day continues into the afternoon and the stimulant wears off. You can tell because psychotropic-induced dilation of the pupils for most people on stimulants is the most pronounced in the afternoon.

But what happened if that neurotransmitter depletion persisted? That's basically the first 2-4 weeks after you stop taking stimulants. Your brains neurotransmitter levels adjusting to the change. The only difference is that with divalproex on-board, while your serotonin and dopamine levels are in the dumps and you're feeling helpless and angry, valproate is increasing GABA levels and soothing the brain much in the same way that alcohol would actually.

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  • 2 weeks later...
On 4/27/2020 at 7:51 PM, browri said:

@the maze runner well I'm sure you know that methylphenidate and valproate are two completely different compounds and work very differently in the brain and even feel quite different to the individual, they can both mediate similar downstream changes.

For example, bupropion (Wellbutrin) is regarded as a much more stimulating antidepressant and is structurally related to amphetamines and other stimulants like methylphenidate. It is a norepinephine-dopamine reuptake inhibitor like stimulants and a modest releasing agent of these neurotransmitters as well. This causes desensitization of the dopamine system and is inherently stabilizing as a result. The same concept is applied with serotonergic antidepressants and also explains why they can make things worse in the beginning (insomnia, increased anxiety, irritability). Serotonergic activation can mediate many of our mental illnesses. So ramping that up and desensitizing the brain to that signaling can quiet the downstream thought processes.

Where stimulants and bupropion stabilize the dopamine system via increased dopamine signaling and desensitization much like serotonergic antidepressants, valproate on the other hand actually attempts to directly calm the brain on various different levels.

1. It inhibits GABA transaminase and succinate-semialdehyde dehydrogenase which degrade GABA in the brain. Because GABA is the main calming/"depressant" neurotransmitter in the brain, this causes an increase in basal GABA levels.

2. It modulates but generally increases the activity of glutamate dehydrogenase, which would catalyze the conversion of glutamate back into GABA. Because glutamate is a primary excitatory neurotransmitter in the brain, this has a direct calming effect. Glutamate is implicated in some depressive disorders with marked anxious distress as well as bipolar disorder. By inhibiting GABA's breakdown in #1 and inducing glutamate's conversion into GABA here, further increases in basal GABA levels are realized.

3. It induces monoamine oxidase A which is chiefly responsible for the breakdown of monoamines like serotonin and to a lesser extent norepinephrine and dopamine. This results in lower serotonin signaling.

4. Via some mechanism, it reduces catecholamine synthesis (i.e. norepinephrine and dopamine)

The net results though is that valproate administration can actually INCREASE norepinephrine and dopamine concentrations in certain brain areas and decrease it in others. While these two medications are miles apart, perhaps for you they both mediate similar changes in your brain that make you feel better.

Another possibility is that after continued methylphenidate treatment you may be experiencing a bit of neurotransmitter depletion. This is something that everyone who takes stimulants goes through every day. They start the day with a ramp up in virtually all neurotransmitters, then they plummet as the day continues into the afternoon and the stimulant wears off. You can tell because psychotropic-induced dilation of the pupils for most people on stimulants is the most pronounced in the afternoon.

But what happened if that neurotransmitter depletion persisted? That's basically the first 2-4 weeks after you stop taking stimulants. Your brains neurotransmitter levels adjusting to the change. The only difference is that with divalproex on-board, while your serotonin and dopamine levels are in the dumps and you're feeling helpless and angry, valproate is increasing GABA levels and soothing the brain much in the same way that alcohol would actually.

I was having to go without methylphenidate for a while because of the lockdown and suffered a hellish few days. It's finally arriving tomorrow. I'll add to this tomorrow. Cheers!

Edited by the maze runner
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29 minutes ago, the maze runner said:

I was having to go without methylphenidate for a while because of the lockdown and suffered a hellish few days. It's finally arriving tomorrow. I'll add to this tomorrow. Cheers!

Yeah I tried going without Vyvanse. Managed to get past the first 2 weeks, which were hellish, like you describe. However, at about the 1 month point I just decided that my focus was far better on stimulants than off them. In those few weeks, I forgot so many important things that were also simple things. It was a frustrating few weeks. So I get the feeling.

However, if you make it to a month with no stimulants, you'll find that sometimes you do feel less depressed. Generally though if you're bipolar, stimulants can be stabilizing. So while I felt less depressed at times, when I did feel depressed, it was worse off stimulants than on stimulants, naturally. And I was more likely to oscillate between a happy, content mood and a dysphoric one.

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Sorry I was just a little depressed and stuff. I am back on Methylphenidate and I am in working shape again. @browri I was unable to understand the whole biochemistry of what you read. But I do understand feeling kind of off if you're going off your stimulants, Vyvanse in your case and Methyelphenidate in my case.

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7 hours ago, the maze runner said:

Sorry I was just a little depressed and stuff. I am back on Methylphenidate and I am in working shape again. @browri I was unable to understand the whole biochemistry of what you read. But I do understand feeling kind of off if you're going off your stimulants, Vyvanse in your case and Methyelphenidate in my case.

The most important takeaway I think is that while stimulants are stimulants, they can be stabilizing for a lot of people. So yeah, when you go off of them, for the first 2 weeks you feel miserable. But after that, once your brain really starts getting used to operating without stimulants again, many find that episodic, brief/intermittent moments of depression are less common, that they are generally less depressed. However, it's possible there may be more mood instability. So less depressed, and less stable. This is also why doctors use Wellbutrin as a mood stabilizer in some patients.

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