Lithium

0:02 Lithium is mainly used for the treatment of bipolar disorder,

0:06 which is a mental health condition characterized

0:08 by periods of lowered mood and depression,

0:11 as well as periods of heightened mood and mania.

0:15 Although the mechanism of action is not well understood,

0:18 lithium acts as a mood stabilizer that can

0:21 smooth out the highs and lows they experience.

0:26 All right, almost everyone has ups and downs throughout their life.

0:30 They can feel happy on a sunny day or a bit down when it's raining outside.

0:35 They might also have some extreme highs,

0:38 like when they meet the love of their life,

0:40 and they might even have some pretty serious lows after

0:43 losing a job or a person they were close to.

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1:04 However, in bipolar disorder, which used to be called manic depression,

1:08 the individual has dramatic shifts in emotions, mood,

1:12 and energy levels, involving extreme lows and extreme highs.

1:17 These shifts usually happen over several days or weeks.

1:22 The low moods are identical to those in major depressive disorder,

1:26 also known as unipolar depression.

1:29 Individuals with this feel hopeless and discouraged,

1:32 have a lack of energy and mental focus,

1:35 and have physical symptoms like eating and sleeping too much or too little.

1:42 But along with these lows, they have periods of high moods as well,

1:46 which are called manic episodes or hypomanic episodes,

1:49 depending on their level of severity.

1:52 In a manic state, people feel energetic,

1:55 overly happy and optimistic, or even euphoric with really high self-esteem.

2:01 And on the surface, these might seem like very positive characteristics,

2:05 but when an individual is in a full manic episode,

2:08 these symptoms can reach a dangerous extreme.

2:12 Patients experiencing mania can behave recklessly.

2:15 They can have pressured speech, where they talk constantly at a rapid-fire pace,

2:20 or they might have racing thoughts and feel as if they don't need sleep.

2:25 Manic episodes also include delusions of grandeur.

2:29 For example, they might believe that they are on a personal

2:32 mission from God or that they have supernatural powers.

2:36 Now, the exact underlying cause of bipolar disorder isn't known,

2:41 but it's thought that both genetic and environmental factors play a part.

2:46 Even though there's no cure for bipolar disorder,

2:49 identifying and treating individuals is really important,

2:52 since there's a real danger that the person

2:54 could harm themselves or die by suicide.

3:01 One of the oldest treatments for bipolar disorder is

3:04 also one of the most effective treatments, and that's lithium.

3:08 It can be used as maintenance therapy to decrease

3:11 the frequency and the magnitude of the ups and downs.

3:15 Lithium can also be used in the treatment of acute manic episodes,

3:19 although the treatment of choice is antipsychotics.

3:23 Apart from the treatment of bipolar disorder,

3:25 lithium is also indicated for unipolar

3:28 depression that doesn't respond to antidepressants.

3:32 Okay, but the exact mechanism by which lithium acts still remains a mystery.

3:38 It's thought that lithium regulates the release of neurotransmitters,

3:42 which are signaling molecules in the brain like serotonin,

3:45 that regulate a lot of brain functions like a person's mood.

3:49 Neurotransmitters are released by one neuron, the presynaptic neuron,

3:54 and received by receptors on the postsynaptic neuron.

4:01 Okay, let's zoom into a presynaptic neuron.

4:05 Inositol is a cyclic sugar alcohol that is abundant in neurons

4:09 and is the structural basis of some super important molecules.

4:13 Inositol is first phosphorylated to phosphatidylinositol, or PI,

4:19 which is then phosphorylated again to phosphatidylinositol 4-phosphate,

4:24 or PIP, and a third time to form phosphatidylinositol 4,5-bisphosphate, or PIP2.

4:33 Next, a membrane-bound enzyme called phospholipase C, or PLC,

4:39 splits PIP2 into inositol trisphosphate, or IP3, and diacylglycerol, or DAG.

4:48 IP3 is soluble and diffuses freely through

4:51 the cytoplasm and into the endoplasmic reticulum,

4:55 where it opens up calcium channels to release stored calcium into the cytoplasm.

5:00 This increase in free intracellular calcium concentration helps to trigger

5:05 the release of the neurotransmitters into the synaptic cleft.

5:09 All right, but we need to recycle the IP3

5:12 back to inositol before it can be used again.

5:15 So, IP3 is dephosphorylated to IP2,

5:19 and then inositol polyphosphate phosphatase, or IPPase,

5:25 dephosphorylates IP2 to IP1, and inositol monophosphatase,

5:31 or IMPase, dephosphorylates IP1 to inositol.

5:36 Both of these enzymes need the cation

5:39 magnesium as a cofactor in order to function, and the theory is that lithium

5:44 inhibits these enzymes by displacing the magnesium.

5:48 This way, IP3 doesn't get recycled back into inositol,

5:52 and we end up with decreased neurotransmitter release.

5:59 Okay, now lithium is taken orally, and it's absorbed rapidly from the gut.

6:05 It doesn't get metabolized by the liver,

6:07 and it's almost exclusively excreted by the kidneys.

6:11 It's important to note that lithium has a narrow therapeutic window,

6:15 which means that there's a thin line between the safe dose and the toxic dose.

6:20 So, lithium requires close monitoring of serum levels.

6:25 For example, in patients with impaired renal function

6:28 or who take medications that reduce GFR, like thiazides,

6:33 NSAIDs, loop diuretics, and ACE inhibitors,

6:37 lithium is not eliminated efficiently, and it's very easy to overdose.

6:45 All right, moving on to side effects.

6:48 Common side effects of lithium are gastrointestinal symptoms like nausea,

6:53 vomiting, diarrhea, and a mild tremor.

6:57 Lithium can also block two super important hormones in our body.

7:02 In the kidneys, lithium blocks the effects of antidiuretic hormone, or ADH.

7:09 ADH normally concentrates urine, so with lithium,

7:12 the kidneys reabsorb too little water from the lumen of the renal tubules,

7:18 causing the body to produce unusually large quantities of urine,

7:22 which is called polyuria.

7:24 Since there's less water in the blood, plasma osmolality increases,

7:29 and that triggers thirst and causes an individual to drink a lot,

7:33 which is called polydipsia.

7:35 This condition is called nephrogenic diabetes insipidus.

7:42 Now, in the thyroid gland,

7:44 lithium blocks the effects of thyroid-stimulating hormone, or TSH.

7:49 TSH normally stimulates the thyroid gland to release the thyroid hormones.

7:55 So, when TSH is blocked, there is hypothyroidism,

7:58 which presents with things like weight gain,

8:01 cold sensitivity, slower heart rate, mental slowness, and constipation.

8:08 Surprisingly, hypothyroidism can also present with a goiter.

8:12 This is due to reactive hypertrophy and hyperplasia of the thyroid

8:16 gland in an effort to compensate for the decrease in thyroid hormones.

8:21 Lithium also causes leukocytosis, or an increase in the white blood cell count,

8:27 but there's no clear mechanism.

8:32 Note that lithium is not safe to use during pregnancy,

8:36 because it increases the risk

8:37 of congenital heart defects like Ebstein's anomaly,

8:41 which means that the leaflets of the tricuspid valve

8:44 are abnormally located lower than normal into the right ventricle.

8:49 Finally, if the levels of lithium increase to toxic levels,

8:53 they can cause acute renal failure, severe neurological symptoms like ataxia,

8:59 or poor coordination of muscle movements, confusion, dysarthria,

9:04 or an inability to speak clearly, coma, and eventually death.

9:12 Now, let's make a simple and fun mnemonic

9:14 that'll help you efficiently memorize these pharmacology facts.

9:18 First, let's have a large lithium battery trying to break into a house.

9:23 He's stuck in the window,

9:25 which represents this medication's narrow therapeutic window.

9:29 For indications, a two-headed polar bear,

9:32 representing bipolar disorder, is investigating this strange object.

9:37 Ignoring the battery is a sad,

9:39 crying man with a force field bouncing medications away,

9:44 for medication-resistant major depressive disorder.

9:48 For the major side effects, let's have Einstein for Ebstein's anomaly.

9:53 He's holding a baby wearing a heart t-shirt

9:56 to help you remember it's a congenital heart defect.

9:59 There are three leaves on Einstein's right pant cuff to help

10:03 you remember the leaflets of the tricuspid valves are displaced downwards.

10:10 Next to them, we have a giant sippy cup for the baby,

10:13 which represents diabetes insipidus.

10:16 The cup is wearing a frozen bow tie for hypothyroidism.

10:21 A bunch of little white blood cells are trying

10:23 to climb the side of the bottle to represent leukocytosis.

10:28 Finally, for the dangerous side effects of an overdose,

10:32 let's have a taxi that's driven by a brain crash through the wall by the window,

10:37 which represents CNS toxicity and ataxia.

10:42 It hit and killed a kidney since it can also cause acute renal failure.

10:51 All right, as a quick recap.

10:54 Lithium is primarily used as a mood stabilizer for people with bipolar disorder.

10:59 Lithium has a narrow therapeutic window

11:02 and requires close monitoring of blood levels.

11:05 Common side effects of lithium include GI symptoms,

11:09 tremor, nephrogenic diabetes insipidus, hypothyroidism, and leukocytosis.

11:17 Lithium also has teratogenic effects and can

11:19 cause congenital heart anomalies like Ebstein anomaly.

11:24 Lithium toxicity can lead to acute renal failure in severe CNS symptoms.

11:31 But wait, there's more.

11:33 Here's a mind map with all of the mnemonics.

11:36 Go ahead and pause the video so you can test yourself to see what you remember.

11:44 Stay tuned for the answers after the credits.

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