Antidepressants

[pattismith]

It's possible I guess. Certainly for many years I had moderate-to-severe generalized anxiety disorder (GAD), and GAD might be due to high NMDA or low GABA (NMDA excites neurons and GABA relaxes neurons).

But is is hard to increase the GABAergic system in a safe way. Benzodiazepines can do it, but have issues of tolerance and withdrawal.

Kava kava may be the best option: this increases the number of GABA binding sites over time.



My anxiety levels greatly increased after catching coxsackievirus B4. It's interesting that CVB4 might trigger an autoimmune attack on the enzyme GAD65, which synthesizes GABA for neurotransmission. I posted about this in this post.

It may be that the amitriptyline you take helps with rising GABA.

Did you ever try GABAergic drugs like Gabapentin or Pregabalin?

These drugs are used in restless legs syndrome, an hyperarousal state with low GABA and low dopamine, (And maybe high glutamate and low adenosine)

Any way, if I had low GABA, I would look into my iron status. Both non anemic iron deficiency and iron overload can produce lower GABA inhibition.

Sources:

Restless legs syndrome (RLS) is a chronic neurological disorder that interferes with rest and sleep.

It has a wide spectrum of symptom severity, and treatment is started when symptoms become bothersome.

Dopamine agonists and calcium channel apha-2-delta antagonists (gabapentin, gabapentin enacarbil and pregabalin) are first-line treatments; calcium channel alpha-2-deltas are preferred over dopamine agonists because they give less augmentation, a condition with symptom onset earlier in the day and intensification of RLS symptoms.

Dopamine agonists can still be used as first-line therapy, but the dose should be kept as low as possible.

Iron supplements are started when the serum ferritin concentration is ≤75µg/L, or if the transferrin saturation is less than 20%. For severe or resistant RLS, a combined treatment approach can be effective. Augmentation can be very challenging to treat and lacks evidenced-based guidelines

Restless Legs Syndrome: clinical features, diagnosis and a practical approach to management (bmj.com)

Iron deficiency is closely associated with altered GABA metabolism and affective behavior.

While mutation in the hemochromatosis (HFE) gene disrupts iron homeostasis and promotes oxidative stress that increases the risk of neurodegeneration, it is largely unknown whether HFE mutation modifies GABAergic homeostasis and emotional behavior.
.....

Taken together, our results suggest a putative role of HFE in regulating labile iron status in the brain, and mutation in H67D perturbs redox-methylation status, contributing to GABAergic dysfunction.—

Brain iron loading impairs DNA methylation and alters GABAergic function in mice - Ye - 2019 - The FASEB Journal - Wiley Online Library

In addition to the well-known dopaminergic involvement in RLS, previous studies pointed out that Brain Iron Deficiency brings also a hyperglutamatergic state that influences a dysfunctional cortico-striatal-thalamic-cortical circuit in genetically vulnerable individuals.

However, the enhancement of arousal mechanisms in RLS may also be explained by functional changes of the ascending arousal systems and by deficitary GABA-mediated inhibitory control.

Very recently, it was also suggested that BID induces a hypoadenosinergic state in RLS, thus possibly providing a link for a putative unified pathophysiological mechanism accounting for both hyperarousal and sensory-motor signs.

The neurophysiology of hyperarousal in restless legs syndrome: Hints for a role of glutamate/GABA - ScienceDirect

These preliminary results suggest that dipyridamole has significant therapeutic effects on both sensory and motor symptoms, as well as sleep. In addition, it provides evidence that hypoadenosinergic mechanisms play a central role in RLS.

Treatment of restless legs syndrome/Willis-Ekbom disease with the non-selective ENT1/ENT2 inhibitor dipyridamole: testing the adenosine hypothesis - ScienceDirect

 

[Hip]

Did you ever try GABAergic drugs like Gabapentin or Pregabalin?

I bought some gabapentin, years ago, but have not really tried it.

I did however try another anticonvulsant drug, lamotrigine, which seemed to have some benefits, but as a side effect I noticed it caused mildly increased suicidal ideation, and a sort of bleaker philosophical outlook (even though I was less depressed when taking lamotrigine). Anticonvulsants are known for promoting suicidal ideation.

Lamotrigine I found also caused increased neck and shoulder muscle stiffness/tension.

On the plus side, I found lamotrigine had a good antidepressant effect, although it did not improve my anhedonia. But it did improve my emotional flatness. I found lamotrigine caused a noticeable increase in my spontaneous desire to chat and socialize with people, in place of my normal desire for social withdrawal and solitude.

Although I found with lamotrigine, my desire and ability focus on medical research was quite diminished (especially my ability to think creatively and laterally about the research), and instead I became more interested in simple and physical organizational tasks around the house, like organizing my desk, or house cleaning. That's not necessarily a negative thing, but it was quite a major change in mental attitude.


According to this study, lamotrigine increases GABA levels after some weeks, to the same degree as gabapentin:

significant elevations in GABA were observed compared with baseline for all three drugs (topiramate 46%, gabapentin 25%, lamotrigine 25%)

 

[Hip]

Any way, if I had low GABA, I would look into my iron status. Both non anemic iron deficiency and iron overload can produce lower GABA inhibition.

My ferritin levels are normal. I tried supplementing with ferrous sulphate for a month, but noticed no benefits.

 

[pattismith]

I bought some gabapentin, years ago, but have not really tried it.

I did however try another anticonvulsant drug, lamotrigine, which seemed to have some benefits, but as a side effect I noticed it caused mildly increased suicidal ideation, and a sort of bleaker philosophical outlook (even though I was less depressed when taking lamotrigine). Anticonvulsants are known for promoting suicidal ideation.

Lamotrigine I found also caused increased neck and shoulder muscle stiffness/tension.

On the plus side, I found lamotrigine had a good antidepressant effect, although it did not improve my anhedonia. But it did improve my emotional flatness. I found lamotrigine caused a noticeable increase in my spontaneous desire to chat and socialize with people, in place of my normal desire for social withdrawal and solitude.

Although I found with lamotrigine, my desire and ability focus on medical research was quite diminished (especially my ability to think creatively and laterally about the research), and instead I became more interested in simple and physical organizational tasks around the house, like organizing my desk, or house cleaning. That's not necessarily a negative thing, but it was quite a major change in mental attitude.


According to this study, lamotrigine increases GABA levels after some weeks, to the same degree as gabapentin:

Lamotrigine is also anti Glutamatergic, and have a bunch of weak inhibitory effects on many receptors, For example adenosine. Do you know if you adenosine is low or high?

I have no effect from caffeine, so I made the hypothesis that my adenosine is low, which is consistent with the RLS findings.

Do you feel any effect with caffeine?

Adenosine A1 receptor agonist is gaining interest in Major Depression.( I'm willing to add Inosine or Dipyridamol to address my low adenosine.)

Mental health needs a balance between all the neurotransmitters. It's not easy to reach back equilibrium once broken.

Suicidal thoughts is a big concern, and you should do something.

It can be the result of low BDNF, too much glutamate, low GABA, low cholesterol, low serotonin...

Neurobiological Basis of Increased Risk for Suicidal Behaviour (nih.gov)

Lamotrigine: Uses, Interactions, Mechanism of Action | DrugBank Online

My ferritin levels are normal. I tried supplementing with ferrous sulphate for a month, but noticed no benefits.

how normal was your ferritin?

 

[Hip]

Suicidal thoughts is a big concern, and you should do something.

I don't have much suicidal ideation these days, so it's not currently a problem. But about 10 years ago I had constant suicidal ideation all day long for many years. This was due to the severe anhedonia I had 10 years ago. Anhedonia is well-known to precipitate suicidal ideation, I think because when you feel no pleasures and no enjoyment from anything (which is the definition of anhedonia), life becomes meaningless. Anhedonia is a dire condition when it it severe.

Do you know if you adenosine is low or high?

I have no effect from caffeine, so I made the hypothesis that my adenosine is low, which is consistent with the RLS findings.

Do you feel any effect with caffeine?

I don't what my adenosine levels are, but caffeine certainly has a stimulatory effect on me.


I sometimes get very mild psychosis symptoms, which are usually transient, lasting only a day. But they are very unpleasant, and so I have focused on finding treatments which help. One of the best treatments I found, purely by accident, is the diuretic drug amiloride. This greatly reduces these mild psychosis symptoms within an hour or two. Other anti-psychosis treatments I found effective are listed at the bottom of this post.

For years I had no idea why amiloride worked, but then I found out that amiloride is an allosteric inhibitor of antagonist binding at A1, A2 and A3 adenosine receptors. Ref: 1 So amiloride in effect acts like an adenosine agonist.

Well, that likely explains why amiloride works for my mild psychosis, as adenosine receptors have been implicated in schizophrenia (psychosis is one of the many symptoms of schizophrenia), and agonism of adenosine A2A receptor helps schizophrenia.

In case you are interested, here is my list of substances that have effects on the adenosine receptors:

Spoiler: Adenosine receptor agonists and antagonists

Notes
Agonism of adenosine A2A receptor helps schizophrenia.
Adenosine A2A receptor agonism exerts a functional antagonism at postsynaptic D2 receptors. 1
A2A stimulation is anti-inflammatory. 1


Adenosine Reuptake Inhibitors
Inosine (also adenosine A3 receptor agonist)
Acetic acid
Progesterone
Ethanol
Hydroxyzine
Tricyclic antidepressants
Propentofylline — may be helpful for schizophrenia. 1
Dipyridamole 200 mg daily — may help schizophrenia. 1 2 (dipyridamole and propentofylline inhibit cellular reuptake of adenosine, and increases extracellular adenosine concentration.).
Allopurinol (gout drug) it inhibits purine degradation and subsequently increases adenosine levels. Helpful in schizophrenia. 1

More: Adenosine reuptake inhibitor - Wikipedia


Adenosine Receptor Agonists
Inosine (adenosine A3 receptor agonist)
D-Limonene (adenosine A2A receptor agonist) — also a potent anti-anxiety, antioxidant and anti-inflammatory (dose 1,000 mg to 3,000 mg per day) 1

More: Adenosine receptor agonist - Wikipedia


Adenosine A2A Receptor Agonists

Adenosine A2A receptor - Wikipedia

D-limonene (half-life 12 to 24 hours, oral bioavailability of D-limonene 43%)
Cannabidiol
Zeatin riboside


Allosteric Modulators of Adenosine Receptors
Amiloride is an allosteric inhibitor of antagonist binding at A1, A2 and A3 adenosine receptor. 1 So amiloride in effect acts like an agonist.


Adenosine Receptor Antagonists
Quercetin antagonist at A1 adenosine receptor. 1

Quercetin is an adenosine receptor antagonist (similar to caffeine), with a Ki value of approximately 2.5μM. Although this is approximately 10-fold more potent than caffeine (25μM) quercetin has failed to confer caffeine like effects when orally dosed at 200mg (despite caffeine being active). This is thought to be related to the poor neural bioavailability of quercetin. 1

Caffeine antagonizes all adenosine receptors: A1, A2A, A2B and A3. 1

 

[Hip]

how normal was your ferritin?

I had two serum ferritin tests in 2011, one was 159 μg/L, and the other 200 μg/L. Normal range is stated as 12 - 275 μg/L.

 

[pattismith]

@Hip thank you for the drug list !

I had two serum ferritin tests in 2011, one was 159 μg/L, and the other 200 μg/L. Normal range is stated as 12 - 275 μg/L.

It's probably fine but research has shown that when ferritin is between 100-300, you can rule out iron deficiency only with other iron markers.
Remember that iron deficiency markers were defined long ago with anemia, so they are not good at evaluate non anemic iron deficiency. Moreover ferritine is not a specific markers as any inflammatory process will raise it's level.

Usually when ferritin is between 100-300, you need to check for example transferrin saturation, it must be superior to 20%

Spoiler: I suspect this marker level should be lowered under 20%

After his chemotherapy and lots of transfusions, my husband got lots of iron chelators.

Then he had new balance problems when walking and his legs started moving during the night in his bed.

His ferritin was high because of the chemotherapy, so transferrin saturation was checked, it was just 20%

He started supplement with iron and eat red meat, and the balance issue disappeared quickly.

 

[Hip]

It's probably fine but research has shown that when ferritin is between 100-300, you can rule out iron deficiency only with other iron markers.

I believe iron deficiency anaemia is normally detected by a full blood count. My full blood counts are normal.

I did at one point try an iron supplement (65 mg daily of elemental iron, as ferrous sulfate) for a few weeks, but noticed no benefits.

 

[pattismith]

I believe iron deficiency anaemia is normally detected by a full blood count. My full blood counts are normal.

I did at one point try an iron supplement (65 mg daily of elemental iron, as ferrous sulfate) for a few weeks, but noticed no benefits.

Keep in mind that:

1- you can have iron deficiency without anemia, it's called Non Anemic Iron Deficiency or Iron Deficiency Without Anemia

2-you can take ferrous sulfate without increasing your ferritin level if you have problem with non heme iron absorption

It's strange but I have chronic iron deficiency, and never had any anemia during my whole life, and
I can't either raise my ferritin enough if I don't eat red meat....

 

[Boba]

@Boba......Hello. This site popped up this a.m., and I just wanted to check and see how you're doing?

Have you been able to find a med that is better for you? It can/does take time and also time for the body to adjust. So many people give up after one or two days when it takes much longer than that for the side-effects to lessen and the body adjust.

@pattismith & @Hip....interesting exchange above. Yours, Lenora.

Hey Lenora, thanks for asking! I‘m slowly improving. I‘m not bedridden anymore, but still housebound. I can do way more stuff than at the beginning. However my girlfriend finally left me as she was not able to cope with the misery of my situation anymore, made her very unhappy. I will keep fighting to get back to my health before covid! Hope you are doing fine!?