Drug of the Month:
Lamotrigine (Lamictal)

What doesn’t get you well keeps you well

Lamotrigine structure

Lamotrigine is an anticonvulsant which has turned about to be the latest, newest, proven effective “mood stabilizer,” by which PL means an agent which prevents mood episodes in bipolar illness.  The studies which proved lamotrigine’s efficacy were conducted over 15 years ago, and now the agent is available as a generic drug.

Clinical efficacy and inefficacy

In the late 1990s, when GlaxoSmithKline (GSK) was preparing its studies of lamotrigine, it had an ambitious agenda:  Multiple randomized clinical trials (RCTs) were conducted for acute mania, acute bipolar depression, and even acute unipolar depression.  Along with two studies in rapid-cycling bipolar illness, it added up to about a dozen randomized clinical trials. 

In all cases, lamotrigine failed.  It was completely ineffective. It was not better than placebo. Luckily for GSK, two  RCTs were conducted in maintenance prevention of mood episodes in bipolar illness. In both cases, lamotrigine worked. It was effective. 

In other words, the drug was proven not to work in any acute mood state, whether mania or depression.  And, it was proven to work in prevention of mood episodes, both manic and depressive.  

Why would lamotrigine prevent future mood episodes, but not improve current ones? This seems like a major paradox for many clinicians because they can’t get out of the mindset of treating acute symptoms. 

The thought always has been that if a drug works short-term, it’ll work long-term:

“What gets you well, keeps you well.”

This common clinical belief was disproven by lamotrigine. It doesn’t get you well, but it keeps you well.  Patients need to take lamotrigine when they’re well, when euthymic, to stay euthymic, not when they’re sick. 

Since these ideas aren't well known, there is a common clinical misconception that lamotrigine is effective for acute depression, whether in bipolar or unipolar illness.  When patients have depressive symptoms, clinicians sometimes increase the dose of lamotrigine as if it will improve depressive symptoms within weeks or months.  The multiple RCTs show that lamotrigine will not help current depressive (or manic) symptoms in that manner. 

These misconceptions about lamotrigine’s acute efficacy were left uncorrected by GSK, which didn't publish the many negative RCTs described above. After a legal verdict against GSK for a different medication (paroxetine), a court order required the company to publish all its negative data on a website.  For a brief period, those data were publicly available on the Internet, from which the PL editor downloaded the results and published them separately.  Without that legal intervention, the results might never have been known due to patent law protection of pharmaceutical research.  

Regarding the maintenance studies themselves, another misconception needs correction: It is sometimes thought that lamotrigine only prevents depression, not mania. In fact, in the combined two maintenance RCTs, lamotrigine was effective in preventing mania more than placebo; it did have mania prevention benefit. It just had more benefit in prevention of depression. 

Biological mechanism

Lamotrigine is a novel anticonvulsant, which raises the seizure threshold via glutamate antagonism. Glutamate is an excitatory neurotransmitter that is distributed throughout the brain. Whether this mechanism is relevant to this agent’s mood effects is  unknown. 

Cl green; N purple

Lamotrigine structure seen on its triazine ring plane, unrelated to other anticonvulsants. Cambridge Structural Database 

Fast facts: Lamotrigine

Typical dose: 50-200 mg/d. 

Biological mechanism: glutamate antagonist

Typical side effects: Rash

Less common but important side effects: Anxiety

Medically important side effects:  Stevens Johnson Syndrome

Clinically proven efficacy: Prevention of mood episodes in bipolar illness

Side effects and dosing

The main concern about lamotrigine is rash.  Non-serious rash happens in about 5-10% of persons; serious rash usually involves Stevens Johnson Syndrome (SJS), which is potentially fatal.  SJS occurs in about 1/5000 adults given lamotrigine, and in about 1/1000 children or adolescents.  These rates assume the standard slow titration of lamotrigine. PL recommends a slower titration than the package insert, developed originally for epilepsy.  

The PL recommendation is 25 mg/d increased every 2 weeks in 25 mg increments -  no faster.  

Risk factors for rash and SJS are rapid titration, other drug allergies (such as antibiotics), and autoimmune conditions (like lupus).  

Of these risk factors, PL would emphasize drug allergies and autoimmune illnesses. Rash risk is higher with drug allergies, and in those cases lamotrigine shouldn't be used as a first-line agent, and if used, the dosing titration should be even slower (such as 12.5 mg every 2 weeks). 

If autoimmune illnesses are present, PL recommends that lamotrigine not be used at all.  A number of cases exist of serious medical harm in autoimmune illness, with immunologic reactions such as SJS and aseptic meningitis.  

The dose range proven effective in RCTs of bipolar illness was 50-200 mg/d.  400 mg/d was studied and was found to be no more effective than 200 mg/d. A common error is to increase lamotrigine dose to 300 mg/d or 400 mg/d, without realizing that these higher doses aren't more effective for bipolar illness. These higher doses only cause more side effects, particularly anxiety and cognitive impairment. 

The PL Bottom Line

  • Lamotrigine is effective for prevention of mood episodes in bipolar illness, but not for acute depressive symptom benefit.
  • There’s no further mood efficacy above 200 mg/d, only more anxiety and cognitive side effects.

PL Reflection

The key to longevity is to have a chronic incurable illness - and take good care of it.

Oliver Wendell Holmes Sr

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