In this discussion, we will go over some facts about bipolar disorders (BDs), symptoms and diagnostics criteria, pharmacology therapy, and patient education.
Bipolar Disorder Facts
Bipolar disorder is a chronic psychiatric disorder characterized by shifts in mood that can range from severe depression to extreme mania. It is most closely related to major depressive disorder, which is also known as a unipolar disorder.
Bipolar disorder is often misdiagnosed because the first phase of bipolar might be depression, and patients get diagnosed with MDD and are not treated appropriately with SSRIs. Remember that all antidepressants have the warning of a manic switch and can cause mania and hypomania in depressive patients (due to GSK3 up-regulation in CNS 20?)
83% of bipolar disorders are classified as severe.
Risk Factors of BD
BP is very heritable. The only other psychiatric disorder with a higher rate is maybe schizophrenia. Other risk factors include illicit drug or alcohol use and major life events for at-risk individuals. The onset is usually during the early to mid-20s.
Concurrent substance abuse is known to increase the risk of violent behaviors.
What Can Worsen or Induce BD
Medical causes:
- Serotonin syndrome
- Hyperthyroidism
- Neurosyphilis
- Traumatic Brain Injury
Drug-Induced:
- Caffeine (no pre-workout!)
- Alcohol
- Corticosteroids
- Illicit substances
- Interfering antidepressants
DSM-5 Criteria for BD
There are three types of BDs: BD Type I (Manic with or without MDD), BD Type II (Hypomanic with MDD), and cyclothymic.
Symptoms of mania (must present with at least 3): DIG FAST
- D – Distractibility
- I – Irritability
- G – Grandiosity
- F – Flight of ideas
- A – Activity involvement excess
- S – Sleep decreased – when the person has mania, they will not sleep, and they will not be tired. In MDD, they will feel tired.
- T – Talkative
Psychotherapy cannot help with these symptoms because nothing is getting through to the patients.
Remember from CNS-19 that mania must last at least 7 days, and hypomania must last at least 4 days and must not be severe enough to impair social functioning or require hospitalization.
Remember that MDD is having at least 5 of the SIG-E-CAPS for at least 2 weeks.
There is one important specifier for BD, which is “with mixed features.” Outcomes for these patients tend to be poor. This is a major predictor of lithium non-response. Do not recommend lithium in these patients.
To be considered rapid cycling, the patients must experience at least 4 mood episodes per year.
BD Treatment Options
Common treatments include medications, ECP, and therapy (depending on where the patient is, it must not be during mania.)
When choosing treatments, we must consider the current phase that the patient is in and what other phases must be treated, such as depression, mania, and mixed.
The medications used in BD treatment are referred to as mood stabilizers.
Ideal components of a mood stabilizer include:
- Anti-manic
- Anti-depressant
- Anti-rapid cycling
- Anti-mixed episodes
- Good for maintenance treatment
There is no medication that contains all of these components, but lithium gets the closest. Lithium has all of the components except anti-mixed episodes.
Lithium
Lithium is a classic and maintenance treatment for BD. It has been shown to help prevent recurrence and re-hospitalization. The use of lithium is alright in depression, but it is very effective in mania.
Lithium is the most effective at preventing recurrence and re-admission in BP-1 and preventing relapse to mania (and depression to a lesser extent.)
The problem with lithium is its narrow therapeutic index. In depression or BD maintenance, the level must be maintained between 0.6 and 0.8 mmol/L to be effective. In acute mania, the level must be between 0.8 and 1.5 mmol/L. Pretty much try to stay at 1 mmol/L
This medication needs to be monitored closely. Symptoms of toxicity include:
- GI complaints and tremors (seen at 1.5-2 mmol/L)
- Confusion and somnolence (seen at 2-2.5 mmol/L)
- Seizures and death (seen at greater than 2.5 mmol/L)
Lithium reaches a steady state after around 5 days, and the level must be drawn 12 hours after the last dose.
Do you know what’s neat about lithium? It has a true linear pharmacology, which means that once you have a stable dose, you can predict the level accurately! (Unless the patients have ESRD)
Lithium also interacts with many common medications (mostly medications that work with kidney function.) This includes:
- Diuretics
- ACEI/ARB
- NSAIDs
- Theophylline
- Caffeine
The renal problem is also why if the patient has persistent GI distress or diarrhea, the loss of volume (impact the renal function) will bump up the SCr, and the lithium level will also bump up.
Lithium is dialyzable but must be done very slowly. Because it is an ion (metal at that), a rapid change in concentration gradient may precipitate arrhythmias.
Lithium Monitoring Parameter
- Kidney function: we must protect the kidney function and avoid renal drugs that would interact with lithium if possible
- We monitor this by BMP or CMP. This must be obtained at baseline. The sample should also be collected again after the 5 days mark (steady state)
- Thyroid function: lithium will affect goiter, leading to low T3 and T4. We can either lower the lithium dose or supplement it with levothyroxine.
- We monitor this by TSH. Also, get this at baseline. Patient with hypothyroidism is expected to have high TSH.
- CBC and electrolytes: These aren’t as important, but can monitor for non-toxic leukocytosis.
- EKG: Because lithium is a positive charge ion, it might be prudent to monitor EKG in patients with cardiac disease
- Pregnancy – lithium can cause problems during the first trimester (organogenesis). We may consider a drug holiday during this time.
Lithium Adverse Effect Profile
- Cardiovascular: Arrhythmias, hypotension
- CNS: Confusion, dizziness, fine hand tremor (specifically intention tremor)
- Dermatologic: Acne, thinning of hair
- Endocrine: Non-toxic goiter, weight gain (10-15 lbs)
- Gastrointestinal: NVD
- Hematologic: Leukocytosis
Lithium has a BBW for NTI and renal.
Patients should be counseled about dietary consistency, drug interactions, S/S of toxicity, pregnancy and lactation.
Carbamazepine
“Always second line“
Carbamazepine is an antiepileptic medication that is approved for acute manic, mixed episodes, seizures, and trigeminal neuralgia. For the treatment of bipolar disorder, carbamazepine is always the second line because it’s as effective as lithium or VPA, and it literally interacts with everything. It has little effect on the relapse to depression.
The reason why it interacts with everything stemmed from its problematic metabolism profile. It is an inducer of CYP3A4 and CYP1A2. Not only does it induces these CYP enzymes, it also an autoinducer, which it means it induces its own metabolism! This is very problematic.
On the side note: it can also reduce the effectiveness of oral contraceptives.
On the second note: it reaches steady state after 4 days.
Carbamazepine Monitoring Parameter and Side Effects
The side effect of carbamazepine includes side effects that you expect to see in any anti-epileptic: hepatic issue, ataxia, sedation, dizziness, nausea. But the hallmark side effects are rash, blood dyscrasia (leukopenia, thrombocytopenia), and hyponatremia (due to autoinduction property.)
Carbamazepine also has BBW warnings are anemia or agranulocytosis (blood dyscrasia) and TENS/SJS (a lot of antiepileptic medications have this)
Side note on TENS and SJS. They are not rash. Rash is only just a symptom of TENS and SJS. These are integumental disorder that can be life-threatening. TENS is where it’s covered more than 30% of the body surface, and has 50% mortality rate. SJS is where it’s covered between 10-30% of the body surface, and has 10% mortality rate. These patients are admitted into the burn unit. Common culprits behind these two are usually antibiotics and antiepileptics. Patients of Asian ancestry with HLA-B*1502 allele have an increased risk.
Due to its ability to cause blood dyscrasia, monitoring CBC is important. Most antiepileptics are teratogenic, which is why we need to monitor for pregnancy as well.
Carbamazepine – “second-line in BD, autoinduction, hyponatremia rash, blood dyscrasia, and pregnancy”
Divalproex/Valproic Acid (VPA)
VPA is another antiepileptic medication. It is a drug of choice for mixed episode. It doesn’t work as well as lithium, but it gets pretty close. It is indicated for the treatment of acute mania or mixed episodes. It is also indicated for the maintenance management of BD. Other indications: seizure disorder and migraine prophylaxis.
VPA is dosed according to weight. This is why there is less need for serum level monitoring. The maximum dosage is 60mg/kg/day. In acute mania, VPA can be titrated rapidly to target (roughly 20mg/kg).
If you don’t remember anything else about VPA side effect, just remember to think about hepatic problem and pregnancy.
VPA Monitoring Parameter and Side Effects
Since VPA is a weight-based dosed medication, monitoring blood level isn’t as important. The medication reaches steady state in around 3 days.
VPA is extensively protein bound, and will compete with other protein bound medications (which is pretty much anything that ends with sodium or acid.) Sometimes VPA can out-compete, which results in a decreased in serum VPA (increase bound VPA.) This occurs with carbamazepine, carbapenems, phenytoin, and rifampin. Sometimes VPA loses out, which results in an increased in serum VPA (decrease bound VPA.) This is seen with guanfacine, salicylates, and topiramate.
Remember, hepatic and pregnancy from before?
This is why we need to have a baseline LFTs and urine pregnancy test before starting the medication.
VPA can also cause thrombocytopenia (dose-dependent – risk goes up with higher dose, greater than 110mcg/mL in female and 135 in male.) This is why we also need to monitor CBC.
VPA has two BBWs. One with hepatic failure, and the other with pancreatitis.
Coming back to pregnancy, VPA is one of a very small group of medication that has dual pregnancy rating, which depends on the indication. VPA has an X for migraines and D for epilepsy and BD.
VPA is known to cause neural-tube defect and has an influence on the child’s IQ that persists throughout life.
Lamotrigine – another antiepileptic
“Lamotrigine does NOT work for mania.”
For the treatment of BD, we should think of lamotrigine as an antidepressant. Because it does not work for mania, it should not be used as a monotherapy for BD type I.
Lamotrigine Dosing
Lamotrigine also needs to be titrated. This titration is very important due to an increase risk of TENS and SJS. Lamotrigine titration is adjusted every 2 weeks.
Lamotrigine dosing is also affected by other medications. It loses out to inducers like carbamazepine, phenobarbital, and phenytoin, which is why the dose needs to be doubled. Lamotrigine wins out to inhibitors like VPA, which is why the dose needs to be halved.
Lamotrigine Side Effects
Lamotrigine has the same side effects as any other antiepileptic: headache, dizziness, sedation, tremors, and fatigue. The hallmark ADR of lamotrigine is rash.
This is why lamotrigine BBW is hypersensitivity reactions. This includes potentials for TENS and SJS. It has higher prevalence in children and usually occur in the first 8 weeks of therapy.
Lamotrigine is pregnancy category C and will enter breast milk.
Patients must be adherence to this medication due to titration requirement and risks of TENS and SJS otherwise. If the patient missed more than 5 days of therapy, titration must be restarted.
Second-Generation Antipsychotics (SGAs)
SGAs are utilized a lot in schizophrenia. Quetiapine that we have already learned about in major depression disorder is also a part of this class. SGAs are ultra-helpful for patients with bipolar disorder in the acute period, but they utility is less clear for long-term use.
SGAs are mostly used in combination with a mood stabilizer (VPA, lithium), and it is shown that a combination is better than either monotherapy alone.
Advantages of SGAs are:
- Most are once daily dosing (except ziprasidone and asenapine)
- More desirable effect in pregnancy than antiepileptics and lithium
- Much easier titrate and can be done more much rapidly than lithium or lamotrigine
- Wider therapeutic index and overdose can be less severe compared to lithium and antiepileptics
The bad? SGAs have a lot of problems with metabolic symptoms
Most SGAs can be used for mania and mixed episodes – olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole. (All except lurasidone and asenapine)
Only three are useful for bipolar depression: olanzapine, quetiapine, lurasidone
SGAs Side Effects
As mentioned before, the primary problem with SGAs is metabolic symptoms. This includes:
- Weight gain
- Dyslipidemia
- Elevated fasting blood glucose
- Hypertension
Ziprasidone, aripiprazole, and asenapine are a little nicer with these, but they still have some side effects.
SGAs have a BBW for elderly patients with dementia-related psychosis (not BD-related psychosis). SGAs may increase the risk of death in these patients.
Other side effects are: sedation, QTc prolongation, dizziness, and neuroleptic malignant syndrome (<1%)
Other MISC Agents:
DO NOT USE first-generation antipsychotic (FGA) for bipolar treatment.
Benzodiazepines
They are mainly there to help with sleep during both mania and depressive phases. Mostly used during the acute phase where we’re trying to control the symptoms and taper off during the continuation phase.
Antidepressants (SSRIs, SNRIs, TCAs)
Antidepressants should not be used in BD.
The only scenario for use is when the patient PRIMARILY present in depression and their depression cannot be controlled with other agents.
The reason to avoid the use of antidepressants is due to their ability to cause a manic-switch (a class warning). This means that the use of antidepressants can trigger a manic episode in BD patients.
If the decision to use antidepressants is made, the patient must meet these three criteria:
- Must be on mood stabilizer as well
- Must not be in a manic or mixed episode
- The treatment is only for acute short-term treatment of BD depression
Discontinue the antidepressants once patient achieve full remission of depressive symptoms for the next 6-8 weeks.
AVOID paroxetine at all cost in these patients because there is a negative trial data. MAOIs, TCAs, or venlafaxine have higher rates of manic-switch.
BD Treatment Goal:
We always try to achieve a full remission, which means that there is no significant signs or symptoms for 2 months. Partial remission or residual mood symptoms at initial recovery are associated with higher risk of recurrent mood episodes.
The three phases of treatment are: Acute (sleep and euthymia, 3-drugs treatment of BZDs, mood stabilizer, and SGA), continuation (cut back on BZD and try for monotherapy), maintenance phase (stable for 3 months – try for monotherapy)