How does lithium work?

Ah, lithium; it’s been our gold-standard treatment for bipolar disorder for many years, and can work for people who have failed other drug trials. It is also one of the only drugs known to decrease the risk of suicide1. But how does it work?

It’s a bit more complicated to understand than, for example, an SSRI (which, ultimately, increases serotonin in the synapse, through a fairly intelligible mechanism of stopping reuptake). Despite knowing since 1949 that lithium was an effective treatment for bipolar disorder, we still don’t fully understand its mechanism of action.

There are a lot of signalling pathways in the brain.

One of the difficulties in determining this is that lithium goes everywhere in your body. Within the brain, it can cause an absurd number of changes through numerous signalling pathways. Like other drugs, it can cross the brain-blood barrier (an important quality for psychiatric medications, since they target the brain) but, uniquely among psych meds, it can also enter your intracellular space — hiding inside your cells, instead of just floating around in your blood.

It is excreted by the kidneys in urine, although it is also known to be excreted in human sweat and tears2. (I’ve had hyper-salty tears caused by lithium every so often.)

Lithium appears to increase the concentration of some neurotransmitters (potentially serotonin and GABA) while moderating the effects of dopamine and norepinephrine through its effects on voltage-gated channels3. This action causes a broad cascade of effects throughout the entire brain that restores balance in people with bipolar disorder. Lithium can get into any cell in your body, and it goes inside your neurons (brain cells) too. This is how it affects voltage-gated channels and moderates the activity of all neurotransmitters.

Although we usually call it a mood stabilizer, it’s not related to any other drug we put in this class, since it is not an anticonvulsant. Lithium is probably most accurately classified as a neuroprotective drug4, like memantine (a drug typically used for Alzheimer’s disease). There is even some speculation that memantine could augment the effect of lithium, due to its similar mechanism of action, but specific to the NMDA receptors.

A key point to understanding the pharmacodynamics of lithium is that lithium, in the human body, can use the same transporters as sodium. It fits where sodium should go — therefore, it exits cells through active transport systems designed for sodium, but at about half the speed of sodium. The similarity of lithium and sodium explains why lithium is excreted by the kidneys and not metabolized by the liver.

a) lithium salts; b) sodium salts

This is also why activated charcoal will not absorb lithium. Your body sees it as a metallic salt (it has a positive charge), and metals (or charged ions) are not attracted to charcoal. In addition, the similarity of sodium and lithium creates a sort of sodium-lithium ecosystem in your body; if you maintain a steady dose of lithium but drastically reduce your intake of sodium, your lithium levels can rise to toxicity.

References

  1. Kessing, L. V., Søndergård, L., Kvist, K., & Andersen, P. K. (2005). Suicide risk in patients treated with lithium. Archives of General Psychiatry, 62(8), 860–866. https://doi.org/10.1001/archpsyc.62.8.860
  2. Fraunfelder, F. T., Fraunfelder, F. W., & Jefferson, J. W. (1992). The effects of lithium on the human visual system. Cutaneous and Ocular Toxicology, 11(2), 97–169. https://doi.org/10.3109/15569529209042704
  3. Lenox, Robert H., H. C.-G. (2000). Overview of the Mechanism of Action of Lithium in the Brain: Fifty-Year Update. 61.
  4. Gray, J. D., & Mcewen, B. S. (2013). Lithium’s role in neural plasticity and its implications for mood disorders. Acta Psychiatrica Scandinavica, 128(5), 347–361. https://doi.org/10.1111/acps.12139

One bipolar person’s drug regimen

Currently, I take 8 medications for psychiatric reasons. I’ve also been on many others — including most of the atypical antipsychotics, several anticonvulsants, antidepressants, and more. These are my current drugs ranked in terms of how essential they are (if, for example, I could only get some of them, perhaps due to a catastrophe):

  1. Lithium — Big Pharma has yet to come up with something better. It could never be patented, it wasn’t paid for by anybody. It actually works. And it’s all-natural. But also, it sucks. Nature is brutal.
  2. Haldol — Indispensable, though I might be switching to Thorazine in the near future. I don’t picture myself living without an antipsychotic again. Typicals seem to work better for me than atypicals did, though I’ve notably NOT tried Risperdal (even though it’s a good fit for my symptoms) or clozapine. Both were considered, though.
  3. Ativan (lorazepam) — My symptoms tend to cluster around anxiety, insomnia, and irritability — maybe paranoia — all things helped by benzodiazepines. If it were not so problematic, I might have ranked it #2. It’s the best immediate symptom relief I can get aside from maybe sublingual Zyprexa (olanzapine).
  4. Adderall — I would never actually achieve anything in life without Adderall. That said, my need to do something with my life is inherently superseded by my need to be alive, which is why it ranks #4.
  5. Lamotrigine (Lamictal) — An anticonvulsant medication. It seems to be doing something, because I become depressed without it. Though I’m not exactly sure what it’s doing.
  6. Gabapentin — I’m supposed to be using it for anxiety to offset my lorazepam use. It’s also useful for severe headaches. I still feel the pain, but I kind of don’t care, like the pain just doesn’t command my attention.
  7. Clonidine — It’s a blood pressure med, but I’m using it for insomnia. I cycle through medications for insomnia because they all lose their effectiveness eventually. I haven’t been on clonidine before so I don’t know how long it will be useful for. Other drugs I’ve used for sleep: Trazodone, Remeron, Ativan, Seroquel (and other atypical antipsychotics)…
  8. Diphenhydramine (Benadryl) — An OTC drug! The original antihistamine. I take it as 50mg softgels (two of them, which is slightly more than the bottle indicates — consult your doctor). Sometimes works for sleep, not super reliable and fades quickly. Useful if I have a cold or flu because Sudafed is not the best choice for my wiring. Also potentially protective against Haldol-induced side effects. So overall, something I take regularly, but not every day.

Anyone want to share their regimen?


What is the goal of psychiatric medication?

The goal of medication isn’t to make everyone neurotypical. That would be boring as fuck. — Dr. Coats (my psychiatrist)

Different psychiatrists no doubt have different philosophies about the point of psychiatric medication, and different patients have their own goals for treatment which naturally vary. To some people, bipolar disorder is a gift to be tamed; to others, it’s a curse to be extinguished. Regardless of whether you choose to take medication for bipolar disorder or not, you surely have your reasons for doing so. Many of these reasons seem to hinge on what the perceived goal of treatment is.

Some goals are specific: for example, “I’d like to be able to go back to school and get my degree”. Some goals, on the other hand, are more vague: “I’d like to be well again”. What does it mean to be well? Certainly, it means different things to different people.

As my psychiatrist, Dr. Coats, has said, the goal of psychiatric medication isn’t to make everyone neurotypical. There are some psychiatrists who may believe that the optimal outcome for everyone looks like neurotypicality (the complete suppression of bipolar symptoms to look like a “normal” person), but for many people with bipolar disorder this isn’t one of their goals. Furthermore, for many people with bipolar disorder it simply won’t happen.

This tends to happen.

One study that followed 258 outpatients, all of whom were taking medication, for one year found that 63% had four or more mood episodes within the year.1 26% were ill for more than 3/4 of the year. It seemed that medication was more effective at controlling mania than depression, as participants spent 3 times more time in depressive states than in manic states. A wide variety of drugs were prescribed to participants in this study, including mood stabilizers, anticonvulsants, antidepressants, benzodiazepines, and thyroid medications. The average participant took 4 different medications. Despite this, only 11% of participants were virtually free of mood symptoms. 89% experienced symptoms to some degree.

The study identified many subgroups of bipolar participants, each with a distinct pattern of recurrence (or non-recurrence) of mood symptoms. For example, of the 26% who were ill for 3/4 of the year or more, there were several subgroups: A) ultra-rapid cyclers who were essentially ill for the entire year, B) those with predominant depressive episodes (but experienced mood cycling), C) those with predominant manic episodes, and D) those who had chronic persistent depression with very little cycling.

Based on which pattern is most accurate to describe a given individual, it would be appropriate to adjust one’s goals and expectations for treatment with medication. When I’m ill, I’m closest to pattern A. My goals include slowing down my cycling, reducing the severity of mood symptoms and suicidal thoughts, suppressing my impulsivity and anger, and sleeping regularly each night. For someone with pattern D, goals might look a bit different.

Me without medication

I think it’s helpful to identify specific goals. This helps you determine if you’ve made any progress towards what you want to achieve, even if you still experience symptoms. For many people, resuming a completely normal life with no symptoms of bipolar disorder may be a futile effort — or an unwanted outcome. Even in my most well periods I experience cyclothymic changes in mood and energy levels. My work style is somewhat erratic, and I might stay up for 2 or 3 days working on a paper until it’s finished, then be unproductive for a month or two. My goals aren’t to extinguish these features. I’m not trying to be neurotypical. I’m trying to protect my life and reduce suffering.

Because while bipolar disorder can come with tremendous gifts, it can also be the source of unbelievable pain and suffering. Only you can decide how to reconcile that in your own life. And if stifling mood episodes completely isn’t your goal, that’s okay. It’s possible that you can still harness the benefits of medication to reduce suffering. I recommend being honest about your goals to your treatment team. A good psychiatrist shouldn’t be forcing neurotypicality onto you. Being bipolar in itself isn’t a bad thing.

Bipolar people are cool!

References

  1. Post RM, Denicoff KD, Leverich GS, et al. Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH Life Chart Method. J Clin Psychiatry. 2003;64(6):680-690. doi:10.4088/JCP.v64n0610

My medication history

I have a long and arduous history with medications. Sometimes, it takes quite some time to strike the right balance with meds and bipolar disorder. This is my own personal review of each medication I’ve been on. There’s a lot! My reviews won’t necessarily be applicable to other people because each person’s response to a medication is different, but hopefully this provides some sense of just how many trials it can take to find something that works.

Stimulants

Adderall — amphetamine salts, a classic stimulant drug. Adderall XR is an extended-release preparation. For some reason the XR didn’t work well for me. I still take the IR daily.

Ritalin — methylphenidate, a different stimulant drug. It has important differences from Adderall and may work better in some people. Slightly different forms of Ritalin go by other names, such as Focalin.

Vyvanse — basically a different kind of Adderall XR,; it is the same molecule as Adderall with an extra group attached that renders it inert, which is then cleaved in the liver over time to release Adderall. To me it feels less effective than Adderall, doses held equivalent.

Mood Stabilizers / Anticonvulsants

Lithium — I’ve taken doses ranging from low to high (currently I take a high dose). Lithium dose is measured by the concentration of it in your blood; the highest dose varies depending on individual differences. You do get frequent blood tests while the ideal dose is being determined, and less after that. It is incredibly effective for many people. Because I’m on a high dose, it sometimes makes me nauseous or makes me throw up, and my hands tremor quite a bit. The cognitive side effects are the worst, but they get better over time. 

Lamictal — lamotrigine. For some people with bipolar disorder, lamotrigine is a better drug than lithium. It is not strongly anti-manic (unlike lithium), but for some this may not be a problem; however, it may be superior at treating bipolar depression. Rarely, it can cause a horrifying skin reaction when you first start taking it (and for that reason, titration takes forever — for me, I believe it took 5 weeks to reach 200mg). Past that initial window, it is considered to have very few side effects.

Depakote — valproic acid. It’s more anti-manic than lamotrigine. It smells terrible, yet apparently it comes in a form designed to put in a patient’s food which psychiatrists call “Depakote sprinkles”.

Gabapentin — I took it for anxiety, and it did put me in a good mood, so I suppose it worked.

Antipsychotics

Seroquel — quetiapine. People pronounce it in wildly different ways, I say “kweh-tie-ah-peen”. It helped with my mixed episode, but eventually it lost effectiveness and I found myself staying awake all night on 800mg (that’s a lot of Seroquel). Basically, it’s good for putting you the fuck to sleep, or at least it should be.

Zyprexa — olanzapine. It made me gain a lot of weight. It was fairly effective, but I had to discontinue it due to problems with my liver and its effect on my metabolism. It’s also pretty good at putting you to sleep. I preferred the sublingual form during my inpatient stays (it’s vaguely citrus flavored) because it made me feel better really quickly when I was agitated.

Abilify — aripiprazole. This drug actually helped me for a long time, and it still seems to have some effectiveness but I developed a facial dyskinesia while taking it. That’s an involuntary muscle movement, in my case of my lower left face. This was thought to be uncommon at first, but it turns out with long-term Abilify use (4 years for me), it’s quite possible. I can’t take any drugs related to Abilify anymore — these include Vraylar (cariprazine) and Rexulti (brexpiprazole). Abilify is not usually good at putting you to sleep, but when I started taking it I was on a dose that was too high for me at the time and I was very somnolent most of the time. 

Geodon — ziprasidone. I felt well but it made me throw up a lot. I discontinued it and got some Zofran from the ER. You have to take it multiple times per day, so you hope it doesn’t put you to sleep. I usually did have to take a mid-day nap.

Latuda — lurasidone. You have to be sure to take it with food. It wasn’t very effective for me. 

Saphris — asenapine. Warning, it only comes in a sublingual form and it’s cherry flavored. Nope. I only took it once and I had nightmares about cherry flavor afterwards.

Clozapine — I didn’t actually take this one, but it was on the table. I chose Haldol instead. It is probably considered the most powerful antipsychotic because it has been shown to break through where other antipsychotics have failed, and it was the first “second-generation” or “atypical” antipsychotic. However, it is quite possibly the single most dangerous drug in psychiatry — the potential side effects include a catastrophic loss of white blood cells, among other serious effects. It’s a “drug of last resort”.

Haldol — haloperidol. Haldol is an older drug, one of the “first generation” or “typical” antipsychotics and it is the most potent among those, also with the highest likelihood to cause dyskinesias (including tardive dyskinesia, which is permanent). These side effects have led to the popularity of the “atypical” drugs listed above, which are less likely to cause dyskinesia. Haldol is very effective for me, and I don’t find it sedating at all (which is a blessing and a curse). Having taken most of the atypicals available in the US (except for clozapine, paliperidone, risperidone, and a couple others that are much more rare), I was surprised at how not sedating it is.

Thorazine — I haven’t taken this one either, but it’s been on the table because of its more favorable side effect profile. It is the original antipsychotic drug, from which tricyclic antidepressants were also derived. It has more action on the histamine receptors than Haldol, making it much more sedating. However, this also makes it less prone to cause troubling dyskinesias — for example, antihistamines are actually a treatment for dyskinesia.

Antidepressants

Prozac — fluoxetine. It’s pretty much the basic SSRI. It didn’t do much for my mood at the time. It’s often used in combination with olanzapine/Zyprexa.

Lexapro — escitalopram. It’s an SSRI, and it has high selectivity to affect serotonin reuptake and not norepinephrine reuptake, in contrast to Prozac (which is not very selective). I took it for anxiety and OCD symptoms; I wasn’t convinced it was effective. It also changed my sexual functioning for the worse. 

Wellbutrin — bupropion. It’s an atypical antidepressant that affects norepinephrine and dopamine uptake. I took it to help with smoking cessation. It did make cigarettes taste bad, but I continued smoking them and within short order the drug made me manic.

Trazodone — an atypical antidepressant and an oldie but goodie. This one puts me to sleep (most of the time), and thank God for that.

Remeron — mirtazapine. Another atypical antidepressant. Usually a sleep drug, sometimes used for straight depression, also a great anti-emetic (anti-nausea drug).

Benzodiazepines

Xanax — the only time I took Xanax was recreationally, but I didn’t feel very enamored with the experience. Xanax is highly addictive, I suppose some people find it euphoric in a way. 

Ativan — it’s like toned-down Xanax, it is quite effective but it’s not as euphoric. It has helped me in ways other drugs couldn’t, although whether I would recommend them would be situational due to the addictive potential.

Valium — I’ve only gotten it in the ER, but it lasts longer than Ativan.

Others

Propranolol — a beta blocker, it helps me with akathisia (a side effect of antipsychotics).

Cogentin — benztropine. An antichonlinergic drug used to treat the side effects of antipsychotics. I didn’t take it for very long.


Should I be afraid to take lithium?

Lithium has a reputation. When I was first prescribed it, I felt a sense of fear and also — somehow — a sense of achievement, like I had won the lottery for crazy. When you hear about lithium, it’s often to stress that it is only for those top shelf mental illnesses; and it is good for that, however, it’s not necessarily true that you’re on the top shelf just because you’re starting lithium. A lot of people take lithium. On some occasions it might be the first medication tried. There are a few things to know about lithium in order to make truly informed choices about what you’re getting into.

It’s highly effective

Lithium is one of the most effective medications for bipolar disorder. Which medication is the best varies by person, and a lot of people have success with anticonvulsants like Lamictal. But for many people, the most effective medication is lithium, and its effectiveness has been well-documented for many years (it was first used in psychiatry in 1949). According to one study, about 30% of people who try lithium witness a complete recovery, while 60% see some improvement.

Unlike some other medications, lithium isn’t just a treatment for symptoms of mania; it actually prevents future mood episodes. Relapses become less frequent and shorter. There is some evidence that lithium has a protective effect in the brain.

Lithium has a decent chance of working for any type of bipolar disorder, but there are some people in particular who are very likely to be lithium responders. Those people tend to have:

  • Fewer hospitalizations prior to starting lithium
  • Later age of onset
  • An episodic course (moods cycle and then resolve for a while, as opposed to chronic cycling)
    • About 44% of people with an episodic course have complete remission on lithium, compared to 15% of people with a non-episodic (chronic) course.
    • In one study, 90% of lithium responders who experienced full recovery had complete remission of mood symptoms in between episodes before starting lithium.
  • Mania occurs before depression (mood cycling starts with mania)
  • Strong family history of bipolar disorder and/or a family history of lithium responsiveness
    • One study found that 35% of patients without a family history of lithium response had a complete recovery (similar to other studies mentioned), but among those with a family history of lithium response, that number jumped up to 67% full recovery.

Yes, you’ll get blood drawn

The dosage of lithium is based on how much lithium is in your blood, not how many milligrams are in the pill. The therapeutic window (the space in between the effective dose and the toxic dose) for lithium is much more narrow than most other drugs, so you’ll have to get blood tests frequently, especially when you’re still trying to figure out what dose is best for you.

If you’re afraid of needles, you will probably overcome that fear.

Because lithium blood levels are the most important factor in dosage, it’s probably pointless to try comparing doses with any bipolar friends. Their minimum and maximum dose is probably different than your minimum and maximum dose, so you’re working with two different scales. The middle of their dose range isn’t the middle of your dose range.

Side effects

No doubt, lithium has side effects. The good news is that if you find a low dose is effective for you, you might experience few or no side effects. If you’re on a high dose, it’s more likely that you’ll experience some side effects. These could include:

  • Hand tremors. This can make your handwriting different, and makes it very hard to put Jello in the fridge.
  • Nausea and vomiting. This tends to happen at quite high doses, and it may be a sign that your dose is too high; however, switching to the extended release version of lithium may help.
    • It’s worth noting that your dose can get too high for a variety of reasons, including dehydration; taking ibuprofren or other NSAIDs (you should probably switch to using acetominophen); or climbing a mountain and reaching a very high altitude. That last one hasn’t happened to me personally.
    • If you do actually vomit, it might be very aggressive vomiting and it always seems to come on suddenly.
  • Brain fog. Attention and memory problems come naturally to bipolar disorder, but lithium makes them worse. You may feel that your brain is just working really slowly, and it’s hard to concentrate or read. (Some people also have visual distortions on lithium that make reading even more difficult. I find it easier to read large print.)

In conclusion

Many people are afraid to take lithium, but some experts argue that it’s actually under-used today due to the public perception of it. So, in my opinion, it’s certainly worth trying. Most people won’t experience too many problems; if you’re on a high dose, you might experience some weird stuff, but to me it’s worth it for reducing my mood symptoms, and all of the weird stuff is manageable if you make some small adjustments to your life.

References

Tighe, S. K., Mahon, P. B., & Potash, J. B. (2011). Predictors of lithium response in bipolar disorder. Therapeutic advances in chronic disease2(3), 209–226. https://doi.org/10.1177/2040622311399173